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Lipid dynamics at dendritic spines

Lipid dynamics at dendritic spines REVIEW ARTICLE published: 08 August 2014 NEUROANATOMY doi: 10.3389/fnana.2014.00076 Carlos Gerardo Dotti *, Jose Antonio Esteban and María Dolores Ledesma * Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain Edited by: Dynamic changes in the structure and composition of the membrane protrusions forming Nicolas Heck, University Pierre and dendritic spines underlie memory and learning processes. In recent years a great effort has Marie Curie, France been made to characterize in detail the protein machinery that controls spine plasticity. Reviewed by: However, we know much less about the involvement of lipids, despite being major Sandrine Betuing, UMRsINSERM membrane components and structure determinants. Moreover, protein complexes that 952/UMR7224, France Liliana Minichiello, University of regulate spine plasticity depend on specific interactions with membrane lipids for proper Oxford, UK function and accurate intracellular signaling. In this review we gather information available Núria Casals, Universitat on the lipid composition at dendritic spine membranes and on its dynamics. We pay Internacional de Catalunya, Spain particular attention to the influence that spine lipid dynamism has on glutamate receptors, *Correspondence: Carlos Gerardo Dotti and María which are key regulators of synaptic plasticity. Dolores Ledesma, Centro Biología Molecular Severo Ochoa, Keywords: dendritic spines, cholesterol, sphingolipids, phosphoinositides, glutamate receptors, synaptic plasticity CSIC-UAM, Nicolás Cabrera 1, Madrid 28049, Spain e-mail: [email protected]; [email protected] INTRODUCTION metabolic enzymes regulate dendritic spine shape and protein function their importance is confirmed and strengthened. We At most excitatory synapses in the Central Nervous System, presynaptic boutons synapse onto small membrane protrusions aim here to review this knowledge focusing the attention on the dynamic lipidomics of dendritic spines. We will also discuss about that emerge from the dendritic shaft: the dendritic spines. how this influences synaptic plasticity through the modulation of Changes in dendritic spine number, size and shape contribute glutamate receptors of the AMPA and NMDA-type (AMPARc and to determine the strength of excitatory synaptic transmission NMDARc). These receptors are instrumental to elicit Long Term (Yuste and Bonhoeffer, 2001; Carlisle and Kennedy, 2005). The remodeling of these membrane protrusions in response Potentiation (LTP) and Long Term Depression (LTD), which are considered the molecular mechanisms underlying learning and to stimuli depends on lipids, which are major components of the membrane with the ability to shape it and modify protein memory (Neves et al., 2008; Collingridge et al., 2010). activities within. However, only recently the contribution of spine lipids has attracted similar attention to that of spine proteins. LIPID COMPOSITION AT DENDRITIC SPINES Pioneer work showing the requirement of glial cholesterol for A relevant question about spine physiology is whether spine synapse formation (Mauch et al., 2001) and the elimination of membrane lipid composition and organization is different to spines upon reduction of cholesterol or sphingolipids (Hering that of the dendritic shaft membranes from which these protru- et al., 2003) triggered research in this field. Technical progress sions emerge. A systematic analysis of spine lipid composition facilitates today the not so long ago impossible analysis of the is lacking due to technical limitations. However, accumulating subtle changes in lipid composition and of the topographical evidence indicates it differs from that of the shaft. This raises distribution of individual lipid species in cellular compartments. questions such as why this specificity is necessary and how it Probes have been developed to label lipid molecules such is achieved, maintained or modulated upon stimuli. Until now, as new generation fluorescent tags (Eggeling et al., 2009) or most of the information on synaptic lipid composition comes modified toxins with specific lipid binding abilities such as the from the biochemical analysis of synaptosomal preparations. theta-toxin or lysenin, which bind cholesterol or sphingomyelin, Functional studies have also highlighted the relevant contri- respectively (Abe et al., 2012). These probes together with bution of certain lipids to spine physiology. From these two advanced microscopy techniques that achieve sub-diffraction types of approaches we now know that cholesterol and sphin- optical resolution (i.e., near-field scanning optical microscopy golipids are enriched in spines. Because of their chemical affinity (NSOM), photoactivated localization microscopy (PALM) these lipids form highly dynamic and heterogeneous membrane stochastic optical reconstruction microscopy (STORM) or nanodomains, the so called rafts, which can be stabilized to stimulated depletion (STED) fluorescent microscopy) allow the form larger platforms by protein-protein or protein-lipid inter- direct observation of the nanoscale dynamics of membrane lipids actions (Pike, 2006). Rafts compartmentalize cellular processes in a living cell (Eggeling et al., 2009; van Zanten et al., 2010; contributing to the accurate spatial and temporal organization Castro et al., 2013). As we gain insight on how lipids and their of molecules required at dendritic spines (Allen et al., 2007). Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 1 Dotti et al. Lipids in dendritic spines Neurotrophin and neurotransmitter receptors (NTRcs) are enriched in these structures (Hotulainen and Hoogenraad, 2010; recruited from extrasynaptic to synaptic sites through association Koleske, 2013). Changes in the amount of filamentous actin to lipid rafts, which reduce receptor lateral mobility at the synaptic (F-actin) mediate long-lasting alterations in spine size and synap- space (Nagappan and Lu, 2005; Fernandes et al., 2010). In fact, the tic efficacy. The repetitive firing of synapses that occurs dur- post synapse has been proposed as a lipid raft-enriched territory ing high-frequency stimulation to induce LTP, promotes actin and certain key structural proteins such as the postsynaptic den- polymerization and spine enlargement (Matsuzaki et al., 2004; sity protein 95 (PSD95) as well as AMPARc dynamically associate Okamoto et al., 2004). Conversely, treatment that weakens synap- to these domains (Perez and Bredt, 1998; Suzuki, 2002; Hering tic efficacy, such as low-frequency stimulation that results in et al., 2003; Suzuki et al., 2011). The tight control of the turnover LTD, causes F-actin loss and dendritic spine shrinkage (Okamoto of phosphoinositides and their derivatives plays also a central role et al., 2004; Zhou et al., 2004). Enlargement and shrinkage of in spine plasticity. We next describe data available on the presence the spine requires the coordination of the actin cytoskeleton of the aforementioned lipids in spines and on their contribution with the membrane. Recent work shows that the most abundant to spine physiology. Hopefully, the already mentioned imaging sphingolipid in neuronal membranes, sphingomyelin (SM), plays techniques based on advanced lipid probes and super-resolution a relevant role in the spine membrane-cytoskeleton crosstalk by microscopy together with most sensitive quantitative measure- modulating membrane binding and activity of main regulators ments (i.e., liquid chromatography coupled with tandem mass of the actin cytoskeleton at synapses: the Rho GTPases. Hence, spectrometry) would contribute to more precisely define the lipid high SM levels lower the amount of type I metabotropic gluta- composition of spines and its changes in real time in living cells. mate receptors (mGluRs) at the cell surface impairing membrane attachment, and therefore activity, of the small GTPase RhoA CHOLESTEROL concomitantly with the inhibition of its effectors ROCK and Profilin IIa. This seems to be the mechanism leading to reduced Pharmacological extraction of cholesterol or inhibition of its synthesis led to the disappearance of dendritic spines in cultured F-actin content and smaller size of spines in mice lacking the acid sphingomyelinase (ASM) gene (Arroyo et al., 2014). Conversely, hippocampal neurons, probably mediated by disruption of the actin cytoskeleton (Hering et al., 2003). This finding defined low SM levels in postsynaptic membranes are responsible for the enhanced activity of the RhoA-ROCK-Profilin I pathway resulting cholesterol as a core component of spines. A series of functional reports have demonstrated the relevance of this lipid for synaptic in increased actin polymerization and dendritic spine size in mice lacking the actin related protein WIP (Franco-Villanueva plasticity. Pioneer work showed that acute cyclodextrin-mediated removal of membrane cholesterol blocks LTP in the hippocampus et al., 2014). Moreover, the dynamic partitioning of RhoA into raft membrane domains, which is enhanced upon stimuli, is (Koudinov and Koudinova, 2001; Frank et al., 2008). On the other dependent on the maintenance of appropriate SM levels at the hand, excitatory neurotransmission, chronic and acute, induces cholesterol loss from synapses, which is recovered after stimuli synaptic membrane (Franco-Villanueva et al., 2014). Ceramide is another major sphingolipid contributing to spine (Sodero et al., 2011, 2012). In the aging brain, lifelong lasting synaptic activity and concomitant metabolic stress contributes to plasticity by virtue of its capacity to favor membrane fusogenicity promoting receptor clustering (Krönke, 1999). The rapid genera- a moderate but irreversible loss of membrane cholesterol (Sodero et al., 2011), which is thought to underlie cognitive deficits tion of ceramide modulates excitatory postsynaptic currents by controlling the insertion and clustering of NMDARc (Wheeler present at this stage of life (Martin et al., 2014). In agreement, cholesterol replenishment restores LTD in hippocampal slices et al., 2009). In agreement, direct additions of synthetic cell- permeable ceramide analogs increase excitatory postsynaptic cur- from aged mice and improves their learning and memory abilities (Martin et al., 2014). The molecular mechanisms by which rents without affecting presynaptic plasticity (Coogan et al., 1999; Fasano et al., 2003). The ceramide-associated enhancement of cholesterol influences postsynaptic plasticity are just beginning excitatory currents is often transient and is followed by sus- to be understood. Thus, impaired LTD in the old produced as tained depression of excitatory postsynaptic currents (Coogan consequence of lower membrane cholesterol can be explained, et al., 1999; Yang, 2000; Davis et al., 2006). These findings to a certain extent, by sustained activity of the PI3K/Akt pathway, in turn leading to inactivation of GSK3b and reduced support complex roles for the spatial and temporal produc- tion of ceramide in regulating neuronal excitability. In addition, AMPAR internalization (Martin et al., 2014). The broad effect of cholesterol on the biophysical properties of the membrane bilayer ceramide contributes to spine maturation by promoting the trans- formation of dendritic fillopodia into mature spines (Carrasco (i.e., viscosity, Renner et al., 2009) may affect the molecular flow in and out of synapses and therefore the mobility and interactions et al., 2012). of NTRc (Fantini and Barrantes, 2009). Changes in the amount of cholesterol at spines might also exert functional effects through PHOSPHOINOSITIDES AND DERIVATIVES cholesterol metabolites. Thus, the most abundant in the brain, Despite phosphoinositides (PIPs) are minor components of 24(S)-hydroxycholesterol, is a potent and selective positive synaptic membranes, their exceptional high rate of metabolic turnover and their compartmentalization make them key players modulator of NMDARc and enhances LTP (Paul et al., 2013). in postsynaptic excitability (Hammond and Schiavo, 2007). The SPHINGOLIPIDS presence at dendritic spines of the enzymes that interconvert Long term stability and dynamic changes in dendritic spines are different PIPs supports a relevant role for these lipids in the intimately linked to the actin cytoskeleton, which is particularly dynamics of these structures. Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 2 Dotti et al. Lipids in dendritic spines Continuous synthesis and availability of phosphatidylinosi- recruits and activates DAG effectors (among them PKC), which tol(3,4,5) triphosphate (PIP3) at the postsynaptic terminal is have been involved in spine maintenance (Brose et al., 2004). DAG necessary for sustaining synaptic function in rat hippocampal molecules are produced in dendritic spines through activation neurons (Arendt et al., 2010). PIP3 shows greater accumulation of postsynaptic receptors, including those of the NMDA type. in spines than in dendritic shafts under basal conditions. Inter- It has been proposed that the rapid and focal generation of estingly, glutamate stimulation promotes spine enlargement and DAG, together with ceramide, triggers the fusion of vesicles and the appearance of filopodia-like protrusions (spinules) projecting insertion of NMDARc subunits into lipid rafts. Based on the bio- from spines (Richards et al., 2005) to which PIP3 redistributes physical properties of DAG, it is likely that the generation of this (Ueda and Hayashi, 2013). Consistent with a key role for PIP3 lipid serves to destabilize the membranes to create fusion points at in spinule formation, blockage or inhibition of this lipid pre- the postsynapse (Wheeler et al., 2009). In turn, phosphatidic acid vent their appearance (Ueda and Hayashi, 2013). The biological (PA) that is generated by DAG phosphorylation, also regulates significance of spinules is not yet established. However, trans- spines together with its effectors. Among them, the alpha-p-21- endocytosis of these protrusions by presynaptic buttons may activated kinase PAK1 promotes spine formation by stabilizing aid postsynaptic membrane remodeling by removing the excess actin filaments through myosin phosphorylation (Zhang et al., membrane at postsynaptic sites (Spacek and Harris, 2004). It was 2005). also proposed that PIP3 signaling at spinules enables new synapses DYNAMISM OF THE LIPID COMPOSITION AT DENDRITIC to form with functional presynaptic boutons contributing to the change in synaptic connectivity. PIP3 could also mediate SPINES: THE ROLE OF LIPID METABOLIC ENZYMES membrane-cytoskeleton crosstalk at spines by virtue of its capac- The aforementioned evidences highlight not only the wealth and ity to regulate the activity of multiple Rho GTPase effectors (Yin specificity of the lipid composition at spines but also its dynamism and Janmey, 2003). Additionally, PIP3 is the upstream regulator and panoply of biological roles. The question remains on how of the Akt-mTOR pathway, which signals activity-dependent reg- this lipid composition is achieved and maintained, or changed, ulation of protein synthesis (Kelleher et al., 2004) and participates in different physiological situations. While still being an open in dendritic and spine morphogenesis (Kumar et al., 2005). question, local recruitment and removal of the different metabolic Appropriate levels and clustering of phosphatidylinositol(4,5) enzymes is a reasonable possibility. In fact, a number of these diphosphate (PIP2) at the postsynaptic membrane, which are enzymes have been localized in dendritic spines, change their modulated by the activities of Phospholipase g (PLCg) and activity upon synaptic stimuli and/or have the ability to modulate PIP5K, are important for synaptic plasticity, both LTP (Trovò NTRc trafficking and function. While the recruitment of certain et al., 2013) and LTD (Unoki et al., 2012). The PIP2-clustering enzymes occurs in response to stimuli others are constitutively molecule myristoylated alanine-rich C kinase substrate (MAR- present at postsynapses. In the following section we describe CKS) critically contributes to this requirement. The effector examples of the contribution of lipid metabolic enzymes to spine domain of MARCKS reversibly sequesters PIP2 on the plasma physiology. membrane, which can be released in response to local increases in intracellular calcium (McLaughlin and Murray, 2005). Low CHOLESTEROL 24-HYDROXYLASE levels of this protein, leading to PIP2 paucity at the mem- The cytochrome P450 enzyme, cholesterol 24-hydroxylase brane, promote the age-related impairment of synaptic plasticity (Cyp46A1) is selectively expressed in the brain, where it is (Figure 1). Hence, its overexpression in the hippocampus of old responsible for cholesterol oxidation and eventual excretion to mice or intraventricular perfusion of MARCKS peptide result in the general circulation (Lund et al., 1999). Pyramidal neurons enhanced LTP and improved memory (Trovò et al., 2013). On of the hippocampus and cortex, Purkinje cells of the cerebellum, the other hand, MARCKs appears to be a key molecule in spine and hippocampal and cerebellar interneurons show particularly morphogenesis promoting the transition from thin immature high levels of this enzyme, which is preferentially localized in dendritic spines to larger, more stable mushroom by controlling the endoplasmic reticulum (ER) of dendrites and cell bodies actin cytoskeleton (Calabrese and Halpain, 2005). In agreement, (Ramirez et al., 2008). Cyp46A1 contribution to synaptic plas- MARCKs deficient mice show impaired LTP and spatial cogni- ticity is supported by the observations that mice lacking this tion (McNamara et al., 1998; Hussain et al., 2006). Association enzyme present impaired learning and hippocampal LTP (Kotti of MARCKS to the membrane is necessary for its ability to et al., 2006) while mice overexpressing human Cyp46A1 present crosslink F-actin (Calabrese and Halpain, 2005). Membrane levels improved spatial memory (Maioli et al., 2013). Increased levels of of cholesterol, to which MARCKs can bind, would mediate this Cyp46A1 parallel the mild but significant cholesterol reduction in association. Evidence suggests that indeed defective MARCKs- membranes of the hippocampus of old rodents and of hippocam- induced PIP2 clustering in old synaptic membranes responds to pal neurons aged in culture (Martin et al., 2008; Sodero et al., the reduction of cholesterol levels during aging (Trovò et al., 2013; 2011). In turn, knockdown of the enzyme prevents glutamate- Martin et al., 2014; Figure 1). mediated cholesterol loss (Sodero et al., 2012), supporting a Besides PIPs themselves, PIP derived second messengers such cause-effect relationship between cholesterol reduction in the as Diacylglycerol (DAG) and 1,4,5-triphosphate (IP3) generated aged and Cyp46A1 increased activity. Biotinylation, electron by the hydrolysis of PIP2 by PLC, are also important in dendritic microscopy and TIRF analysis indicated that Cyp46A1 is present spine organization and function. Unlike IP3, which is released in spines of hippocampal neurons and that, upon stimulation, into the spine cytoplasm, DAG is embedded in the membrane and a close approximation occurs between the site of residence of Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 3 Dotti et al. Lipids in dendritic spines FIGURE 1 | Cholesterol regulation at spines upon glutamate stimulation. constitutive high intracellular calcium and irreversible cholesterol loss due to Acute glutamate stimulatory conditions lead to loss of membrane cholesterol. lifelong lasting synaptic activity leads to reduced membrane-associated The mechanism proposed involves glutamate induced rise in intracellular MARCKS, which affects synaptic plasticity by several mechanisms: (1) Ca++ leading to the approximation/apposition of ER membranes to the impaired MARCKS-mediated actin dynamics; (2) reduced membrane synaptic plasma membrane. This allows Cyp46A1, whose active site is in the clustering of PIP2; and (3) high PI3K activity resulting in reduced lumenal side of the ER, to oxidize cholesterol present in the exoplasmic glutamate-mediated Akt dephosphorylation and GSK3b activation. The later leaflet that is released as hydroxycholesterol. In the aging context, contributes to the impaired AMPARc internalization and LTD in aged neurons. the enzyme (the ER) and the plasma membrane, suggesting that enriched in hippocampus made it a likely candidate to modulate this could be the mechanism by which cholesterol is removed plasticity (Hofmann et al., 2000). In support, abundant NSM from the plasma membrane (Sodero et al., 2012). The increase has been found in synaptic membranes (Arroyo et al., 2014). in surface Cyp46A1 after stimulation supports this notion, and The rapid generation of ceramide by NSM modulates excitatory the higher production of its metabolite 24S-hydroxycholesterol postsynaptic currents by controlling the insertion and clustering in stimulated neurons indicates that the pool of the enzyme of NMDARc (Wheeler et al., 2009). In addition recent work shows that increase at the plasma membrane is active. Not surprisingly the ability of this enzyme to modulate spine actin cytoskeleton. for an ER-resident protein, the process of Cyp46A1 mediated Hence, activation of NSM corrects the abnormally low size and 2C cholesterol loss requires high levels of intracellular Ca and a F-actin content of dendritic spines in mice lacking the acid functional ER-plasma membrane communication via the stromal sphingomyelinase, which present high SM synaptic levels, by interaction molecule 2 (STIM2; Sodero et al., 2012). It has been enhancing the RhoA pathway (Arroyo et al., 2014). Conversely, 2C proposed that high levels of Ca elicit such communication NSM inhibition restores normal RhoA activity and diminishes bypassing the Golgi apparatus. This process would be consistent the abnormally increased size and F-actin levels of spines in with the observation that the distance between the ER and the neurons of mice lacking WIP (Franco-Villanueva et al., 2014; plasma membrane can be as small as 10 nm (Pichler et al., Figure 2). This actin-related protein has the ability to sense the 2001; Lebiedzinska et al., 2009) and that NMDARc stimula- levels of F-actin to which it can bind. It has been proposed that tion produces a transient and reversible fission of ER tubules WIP modulates SM amount at the spine membrane by RhoA (Kucharz et al., 2009). This mechanism provides an efficient, mediated transcriptional control of the NSM, thus controlling temporally and spatially controlled, mean to change postsynaptic the spine response to actin polymerization stimuli (Franco- membrane lipid composition (Figure 1). Whether lipid metabolic Villanueva et al., 2014). This places NSM at a key position to enzymes other than Cyp46A1 follow the same mechanism is mediate membrane-cytoskeleton crosstalk at spines. It remains unknown. to be determined whether the enzyme levels and activity could be modulated at synapses by a local transcriptional control NEUTRAL SPHINGOMYELINASE-2 mechanism. The observation that activation of NSM with Among the sphingolipid metabolic enzymes the Neutral dexamethasone corrects actin related anomalies in isolated sphingomeylinase-2 (NSM) has been directly related to spine synaptosomes argues in favor of this possibility (Arroyo et al., size and to postsynaptic function. NSM is the main responsible 2014). If true, the question arises on whether, similar to those of SM degradation and conversion to ceramide at the plasma of many actin related proteins, mRNAs of lipid metabolic membrane (Stoffel, 1999). Its rapid kinetics and location enzymes are present at synapses to facilitate the immediate spine Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 4 Dotti et al. Lipids in dendritic spines FIGURE 2 | SM and its catabolic enzymes in dendritic spine physiology binding and pathway activation, which diminish spine F-actin content and size. and pathology. SM levels at the postsynaptic membrane modulate These anomalies can be corrected by NSM activation. Conversely, mice membrane binding and activation of the small GTPase RhoA, which in turn lacking the actin related protein WIP show constitutively active NSM leading modulates F-actin content through its effectors ROCK and profillin 2A. This to reduced SM levels, which enhance RhoA membrane binding and pathway molecular mechanism controls dendritic spine size. The SM catabolic activation resulting in bigger dendritic spines with higher F-actin content. enzymes ASM and NSM are involved in this process. Hence, mice lacking Spine anomalies could explain the cognitive deficits observed in ASMko mice, ASM show abnormally high SM levels in their postsynaptic membranes that which are a model for Niemann Pick disease type A, and those of individuals lower the amount of cell surface mGluRs. This impairs RhoA membrane carrying mutations in the region encoding for WIP. remodeling in response to stimuli. Alternatively, NSM would Instead, CPT1C may influence the generation of ceramide from translocate to the synaptic plasma membrane upon stimulation. the sphingosine pool through the salvage pathway and/or on its This is supported by evidences in non-neuronal cells showing degradation. CPT1C deficiency increases immature filopodia and that a stress-mediated PKC mechanism induces the appearance reduces mature mushroom and stubby spines, while not affecting of the enzyme at the plasma membrane (Clarke et al., 2008). total spine number or spine head area. These effects on spine The possibility that not only NSM but also its analog enzyme, maturation can be restored by ceramide addition (Carrasco et al., ASM, regulates SM levels at the postsynaptic membrane is not yet 2012). Consistent with the role of CPT1C on the transforma- clarified. The presence of ASM in spines has not been reported. tion of dendritic filopodia into mature spines, mice lacking this However, the observations that lack of this enzyme leads to enzyme show defects in hippocampus dependent learning abilities reduced spine size and F-actin content (Arroyo et al., 2014) and (Carrasco et al., 2012). that it can function at neutral pH (Schissel et al., 1998) or in PHOSPHOINOSITIDE METABOLIC ENZYMES acidified microenvironments that may exist at the cell surface Several enzymes tightly control PIP turnover at dendritic spines (Bourguignon et al., 2004), support the regulated action of the (Figure 3). Biochemical and imaging experiments demonstrated two sphingomyelinases to control spine SM levels and actin that the phosphatase and tensin homolog deleted on chromosome cytoskeleton (Figure 2). ten (PTEN), which converts PIP3 into PIP2 (Maehama and CARNITINE PALMITOYLTRANSFERASE 1C (CPT1C) Dixon, 1999), is recruited to dendritic spines upon NMDARc The brain specific isoform of Carnitine Palmitoyltransferase 1 but not AMPARc activation (Jurado et al., 2010). NMDARc (CPT1C), modulates ceramide levels in hippocampal neurons activation triggers a biphasic regulation of PTEN mobility in where it is especially enriched (Carrasco et al., 2012). CPT1C is dendritic spines. First, there is a rapid and transient increase located in the ER and has been recently found inside dendritic in mobility independent from PTEN interactions through its spines. The mechanism by which this enzyme, which facilitates PDZ motif. A longer-lasting and PDZ-dependent anchoring of fatty acid transport across intracellular membranes (Wolfgang PTEN to the postsynaptic density follows this phase. This reg- et al., 2006), modulates ceramide levels is still unknown. Acti- ulated mechanism of recruitment of PTEN may provide means vation of de novo synthesis of the lipid has been discarded. to achieve synapse-specific modulation of PIP3 signaling during Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 5 Dotti et al. Lipids in dendritic spines of synaptic stimuli. It has been proposed that lipid signals (i.e., 2-arachidonoylglycerol) generated at dendritic spines by PLC activity, upon activation of type I metabotropic glutamate receptors (mGluRs), diffuse across the synaptic cleft and activate 2C cannabinoid receptors, reducing presynpatic Ca channel activ- ity and inhibiting further glutamate release (Chevaleyre et al., 2006). DAG KINASES Evidence accumulates in support of the notion that DAG- metabolizing enzymes DAG kinases (DGK), which are coupled to synaptic scaffolding proteins, tightly control synaptic DAG concentrations (Kim et al., 2010). Activation of NTRc, including mGluR and NMDARc, induce the production of DAG and its phosphorylation by DGKs, converting DAG into PA. The DGKz isoform has been critically involved in spine maintenance. DGKz is targeted to excitatory synapses through its direct interaction with the postsynaptic scaffold protein PSD-95. Overexpression of DGKz in cultured neurons increases the number of dendritic spines in a manner requiring its catalytic activity and PSD- FIGURE 3 | PIP metabolism in spine plasticity. Activation of NMDARc 95 binding. Conversely, DGKz knockdown reduces spine den- modulate AMPARc trafficking through spatially and timely controlled activity of PIPs and their metabolic enzymes. On one hand, PI3K association with sity (Kim et al., 2009). In agreement, mice deficient in DGKz AMPARc is required for receptor cell surface delivery during LTP. On the expression show reduced spine density and excitatory synaptic other hand, PTEN activity leading to PIP3 downregulation promotes transmission. Time-lapse imaging indicates that DGKz is required migration of AMPARc from the postsynaptic density to the perisynaptic for spine maintenance but not formation (Kim et al., 2009). It has membrane. This depresses AMPARc synaptic responses by promoting been proposed that DAG and PA signaling pathways are integrated receptor endocytosis during LTD. Moreover, signaling pathways initiated by PIP3 or PIP2, in which Akt/mTOR, DAG and IP3 are involved, contribute to within synaptic multi-protein complexes that intersect with small actin remodeling and spine changes in size. GTPases controlling actin cytoskeleton (Tada and Sheng, 2006; Kim et al., 2010). INFLUENCE OF MEMBRANE LIPIDS ON GLUTAMATE plasticity. The enhancement of PTEN lipid phosphatase activ- RECEPTOR FUNCTION AT DENDRITIC SPINES ity is able to drive depression of AMPARc-mediated synaptic responses (Jurado et al., 2010). Consistently, mice with altered Modifications in the number and complement of glutamate- PTEN expression show multiple impairments in synaptic func- sensing receptors in the postsynaptic membrane are key mech- tion including LTP and LTD (Wang et al., 2006; Fraser et al., anisms to adjust strength in excitatory synapses. AMPA and 2008). NMDA-type glutamate receptors are ligand-gated ion chan- The class I phosphatydilinsositol-3-kinase (PI3K) constitu- nels critical for synaptic plasticity (Barria and Malinow, 2002; tively localizes at synapses by means of a direct interaction Malinow and Malenka, 2002; Washbourne et al., 2004). Although between its p85 subunit and the AMPARc (Man et al., 2003). By the identification and characterization of proteins involved in converting PIP2 into PIP3 this kinase ensures the delivery of new the regulation of these receptors has been a productive area AMPARc into spines in response to NMDARc activation (Man of research, there has been less progress in understanding how et al., 2003) and the maintenance of AMPARc clustering at the changes in membrane lipids affect their function. Lipids could postsynaptic membrane (Arendt et al., 2010; Figure 3). modulate glutamate receptor affinity or capacity to bind their lig- The major PIP2 producing enzyme in the brain, the ands by influencing receptor conformation, orientation, subunit phosphatidylinositol-4-phosphate 5-kinaseg661 (PIP5Kg661), composition or oligomerization. Lipids could as well alter the becomes dephosphorylated and associates with the clathrin adap- properties of the channels themselves. Lateral movement and tor protein complex AP-2 at postsynapses upon NMDA receptor endo-exocytic trafficking of NTRcs are essential for glutamate activation (Unoki et al., 2012). This event is necessary to elicit signaling. Lipids are also good candidates to regulate these mem- AMPARc endocytosis and LTD. PLC, which catalyzes hydrolysis brane dependent events. Although we still lack accurate informa- of PIP2, is enriched in spine heads and primarily localized in tion about the differences in lipid composition between synaptic a thin border around the postsynaptic density (Yoshida et al., and extrasynaptic sites, specific lipid changes (i.e., cholesterol 2006). PLC activity is enhanced by NMDARc stimulation and or PIP3 loss) affect the synaptic but not the extrasynaptic pool its blockage impairs LTD (Reyes-Harde and Stanton, 1998). This of AMPARc (Arendt et al., 2010; Martin et al., 2014). Hence, activity is required for changes in postsynaptic structure by lipids could contribute to the balance between synaptic and depolymerizing spine actin and decreasing PSD95 levels. This in extrasynaptic glutamate receptor activity, which is key for synaptic turn promotes AMPARc internalization during LTD (Horne and plasticity. Accumulating evidence supports the view that lipid Dell’Acqua, 2007). PLC has been also related to the termination rafts provide both a spatial and a temporal meeting point for Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 6 Dotti et al. Lipids in dendritic spines receptors and proteins involved in a common pathway facilitating Different studies indicate that AMPARc trafficking depends on their intracellular signaling (Allen et al., 2007). Supporting the PIP metabolism (Figure 3). Direct association of AMPARc with relevance of rafts for glutamate receptor function, different sub- PI3K is required for receptor cell surface insertion and expression units of NMDARc (GluN1A, GluN2A, GluN2B) and AMPARc during LTP (Man et al., 2003). It has been proposed that the (GluA1, 2/3 and 4) have been localized to these membrane mobility of synaptic but not extra-synaptic AMPA receptors dur- domains (Hering et al., 2003; Allen et al., 2007). Because of their ing LTD requires PIP3 depletion (Arendt et al., 2010). Hence, localization in spines and importance for postsynaptic excitatory down-regulation of PIP3, either by overexpression of its pleckstrin transmission we will next comment examples of particular lipids homology (PH) domain or by inhibiting PI3K, impairs PSD-95 influencing AMPARc and NMDARc function. accumulation in spines and promotes AMPARc mobility leading to their migration from the postsynaptic density, where excitatory LIPID INFLUENCE ON AMPARc transmission occurs, towards the perisynaptic membrane within the spine, enabling synaptic depression (Arendt et al., 2010). PIP3 AMPARc mediate most excitatory transmission in the brain, and their regulated addition and removal from the postsynaptic effects are specific for synaptic AMPARc, since it does not affect NMDARc nor extrasynaptic AMPARc. Given PIP3 contribution membrane leads to long lasting forms of synaptic plasticity such as LTP and LTD (Malinow and Malenka, 2002). In addition, to the accumulation of PSD95 at spines, it has been proposed that the lipid favors AMPARc retention via modulation of the PSD95 AMPARc continuously cycle in and out the synaptic membrane independently of synaptic activity. This constitutive trafficking synaptic scaffold. Complementary, enhancement of PTEN lipid involves both exocytic delivery from intracellular compartments phosphatase activity, which turns PIP3 into PIP2, is able to drive depression of AMPA receptor-mediated synaptic responses. This (Gerges et al., 2006), fast exchange with surface extra-synaptic receptors via lateral diffusion (Tardin et al., 2003) and internaliza- activity is specifically required for NMDARc-dependent LTD but not for LTP or mGluR-dependent LTD (Jurado et al., 2010). Fur- tion of the displaced receptors by endocytosis, which is essential to sustain LTD (Carroll et al., 1999; Beattie et al., 2000). Although ther turnover of PIP2 by PLC favors synaptic actin depolymeriza- tion and PSD95 degradation, also contributing to the reduction for most of these effects the specific molecular mechanism has not yet been elucidated, experimental modulation of lipids in brain of surface AMPARc expression and spine remodeling (Horne and Dell’Acqua, 2007). slices or cultured neurons lead to changes in AMPARc localization and electrophysiological behavior. As we next describe, some of LIPID INFLUENCE ON NMDARc these effects received in vivo confirmation in mouse models with genetically or experimentally altered lipid content. NMDARc are heterotetrameric ion channels directly implicated Cholesterol depletion reduces early-AMPA-mediated calcium in LTP and LTD being the predominant molecular device for influx (Frank et al., 2008). It was proposed that this effect was controlling synaptic plasticity and memory function (Bashir et al., not due to a direct influence on the AMPARc channel kinetics 1991; Cui et al., 2004; Li and Tsien, 2009). Studies performed but to altered surface expression of at least a subpopulation of with purified NMDARc reconstituted in liposomes showed that 2C AMPARc. Indeed, cholesterol levels have been shown to modulate membrane stretch reduce Mg blockade of NMDA channel AMPARc surface mobility (Renner et al., 2009) as well as endo- enhancing ion currents (Kloda et al., 2007). As these results were somal dynamics (Hering et al., 2003; Hou et al., 2008). The loss obtained in a minimal system that lacks cellular proteins, they of cholesterol in synaptic membranes of aged neurons impairs unambiguously demonstrate that mechanical deformation of the AMPARc internalization due to PI3K/Akt activation, which pre- lipid bilayer is sufficient to modulate the gating properties of cludes Akt dephosphorylation required for GSK3b activation- NMDA channels (Piomelli et al., 2007). Experimental evidence mediated glutamate receptor endocytosis (Martin et al., 2014). suggests that as much as 60% of NMDARc are located in lipid rafts Quantum-dot-based single molecule tracking analysis showed (Besshoh et al., 2005), which by virtue of their particular physical that reduction of cholesterol also affects GluR2-AMPARc lateral properties might dynamically regulate NMDARc subunit compo- diffusion. These alterations lead to the impaired LTD typical of sition and trafficking. In support of this possibility, changes in old neurons. Consistently, increasing cholesterol levels in vitro or cholesterol content inhibit NMDA-stimulated influx of calcium in vivo by chronic infusion of the lipid restores LTD and cognitive in hippocampal cells in culture (Frank et al., 2004). Cholesterol deficits in the old mice (Martin et al., 2014). reduction redistributes the NMDARc GluN2B subunit, from rafts Little is known about the influence of membrane shingolipids to non-raft membrane fractions (Abulrob et al., 2005). On the in AMPARc function. A positive role for the signaling sph- other hand, the cholesterol metabolite 24(S)-hydroxycholesterol ingolipid Sphingosine-1-phosphate (S1P) in AMPARc-mediated has been recently identified as a potent and highly selective miniature excitatory postsynaptic currents has been reported positive modulator of NMDARc. This hydroxysterol enhances in hippocampal slices. Inhibition of sphingosine kinase (SphK) NMDARc currents and LTP and restores behavioral and cogni- impaired LTP that was fully restored by S1P addition. Con- tive deficits in rodents treated with NMDARc channel blockers sistently, mice lacking SphK show poor memory performance (Paul et al., 2013). It appears that the mechanism underlying (Kanno et al., 2010). However, it has been proposed that these these effects does not involve receptor insertion or transcrip- effects do not take place in spines but correlate with the S1P- tion but direct binding of the lipid to a modulatory site in the induced translocation of S1P receptors to presynaptic terminals receptor. thereby facilitating S1P receptor-mediated signals towards gluta- Dysregulation of brain sphingolipid balance following inhibi- mate release. tion of NSM alters the subunit composition of NMDARc that Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 7 Dotti et al. Lipids in dendritic spines might account for memory impairment following long-term ACKNOWLEDGMENTS inhibition of NSM (Tabatadze et al., 2010). NSM activity mod- The authors thank the support of the Ministerio Español de ulates the phosphorylation of the NMDARc subunit GluN1 on Ciencia e Innovacion (SAF2011-24550 to María Dolores Ledesma, serine 896 promoting the clustering of these modified subunits SAF2013-45392-R to Carlos Gerardo Dotti, SAF2011-24730 to into lipid rafts. It has been proposed that the rapid and focal gen- Jose Antonio Esteban, and Consolider Grant CSD2010-00045 to eration of ceramide upon NSM activation shifts the composition Carlos Gerardo Dotti, María Dolores Ledesma and Jose Antonio of membrane lipids to bring into close proximity GluN1 and its Esteban). kinases PKC and PKA (Wheeler et al., 2009). 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Proc. Natl. Acad. Sci. U S A 102, 6166–6171. cytoskeleton. Annu. Rev. Physiol. 65, 761–789. doi: 10.1146/annurev.physiol.65. doi: 10.1073/pnas.0501881102 092101.142517 Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 10 Dotti et al. Lipids in dendritic spines Yoshida, T., Fukaya, M., Uchigashima, M., Miura, E., Kamiya, H., Kano, M., et al. Conflict of Interest Statement: The authors declare that the research was conducted (2006). Localization of diacylglycerol lipase-alpha around postsynaptic spine in the absence of any commercial or financial relationships that could be construed suggests close proximity between production site of an endocannabinoid, 2- as a potential conflict of interest. arachidonoyl-glycerol and presynaptic cannabinoid CB1 receptor. J. Neurosci. 26, 4740–4751. doi: 10.1523/jneurosci.0054-06.2006 Received: 02 June 2014; accepted: 21 July 2014; published online: 08 August Yuste, R., and Bonhoeffer, T. (2001). Morphological changes in dendritic spines 2014. associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071– Citation: Dotti CG, Esteban JA and Ledesma MD (2014) Lipid dynamics at dendritic 1089. doi: 10.1146/annurev.neuro.24.1.1071 spines. Front. Neuroanat. 8:76. doi: 10.3389/fnana.2014.00076 Zhang, H., Webb, D. J., Asmussen, H., Niu, S., and Horwitz, A. F. (2005). This article was submitted to the journal Frontiers in Neuroanatomy. A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and Copyright © 2014 Dotti, Esteban and Ledesma. This is an open-access article dis- synapse formation through MLC. J. Neurosci. 25, 3379–3388. doi: 10.1523/ tributed under the terms of the Creative Commons Attribution License (CC BY). jneurosci.3553-04.2005 The use, distribution or reproduction in other forums is permitted, provided the Zhou, Q., Homma, K. J., and Poo, M. M. (2004). Shrinkage of dendritic spines original author(s) or licensor are credited and that the original publication in this associated with long-term depression of hippocampal synapses. Neuron 44, 749– journal is cited, in accordance with accepted academic practice. No use, distribution 757. doi: 10.1016/j.neuron.2004.11.011 or reproduction is permitted which does not comply with these terms. Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 11 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Neuroanatomy Unpaywall

Lipid dynamics at dendritic spines

Dotti, Carlos Gerardo; Esteban, Jose Antonio; Ledesma, María Dolores
Frontiers in Neuroanatomy – Aug 8, 2014
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REVIEW ARTICLE published: 08 August 2014 NEUROANATOMY doi: 10.3389/fnana.2014.00076 Carlos Gerardo Dotti *, Jose Antonio Esteban and María Dolores Ledesma * Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain Edited by: Dynamic changes in the structure and composition of the membrane protrusions forming Nicolas Heck, University Pierre and dendritic spines underlie memory and learning processes. In recent years a great effort has Marie Curie, France been made to characterize in detail the protein machinery that controls spine plasticity. Reviewed by: However, we know much less about the involvement of lipids, despite being major Sandrine Betuing, UMRsINSERM membrane components and structure determinants. Moreover, protein complexes that 952/UMR7224, France Liliana Minichiello, University of regulate spine plasticity depend on specific interactions with membrane lipids for proper Oxford, UK function and accurate intracellular signaling. In this review we gather information available Núria Casals, Universitat on the lipid composition at dendritic spine membranes and on its dynamics. We pay Internacional de Catalunya, Spain particular attention to the influence that spine lipid dynamism has on glutamate receptors, *Correspondence: Carlos Gerardo Dotti and María which are key regulators of synaptic plasticity. Dolores Ledesma, Centro Biología Molecular Severo Ochoa, Keywords: dendritic spines, cholesterol, sphingolipids, phosphoinositides, glutamate receptors, synaptic plasticity CSIC-UAM, Nicolás Cabrera 1, Madrid 28049, Spain e-mail: [email protected]; [email protected] INTRODUCTION metabolic enzymes regulate dendritic spine shape and protein function their importance is confirmed and strengthened. We At most excitatory synapses in the Central Nervous System, presynaptic boutons synapse onto small membrane protrusions aim here to review this knowledge focusing the attention on the dynamic lipidomics of dendritic spines. We will also discuss about that emerge from the dendritic shaft: the dendritic spines. how this influences synaptic plasticity through the modulation of Changes in dendritic spine number, size and shape contribute glutamate receptors of the AMPA and NMDA-type (AMPARc and to determine the strength of excitatory synaptic transmission NMDARc). These receptors are instrumental to elicit Long Term (Yuste and Bonhoeffer, 2001; Carlisle and Kennedy, 2005). The remodeling of these membrane protrusions in response Potentiation (LTP) and Long Term Depression (LTD), which are considered the molecular mechanisms underlying learning and to stimuli depends on lipids, which are major components of the membrane with the ability to shape it and modify protein memory (Neves et al., 2008; Collingridge et al., 2010). activities within. However, only recently the contribution of spine lipids has attracted similar attention to that of spine proteins. LIPID COMPOSITION AT DENDRITIC SPINES Pioneer work showing the requirement of glial cholesterol for A relevant question about spine physiology is whether spine synapse formation (Mauch et al., 2001) and the elimination of membrane lipid composition and organization is different to spines upon reduction of cholesterol or sphingolipids (Hering that of the dendritic shaft membranes from which these protru- et al., 2003) triggered research in this field. Technical progress sions emerge. A systematic analysis of spine lipid composition facilitates today the not so long ago impossible analysis of the is lacking due to technical limitations. However, accumulating subtle changes in lipid composition and of the topographical evidence indicates it differs from that of the shaft. This raises distribution of individual lipid species in cellular compartments. questions such as why this specificity is necessary and how it Probes have been developed to label lipid molecules such is achieved, maintained or modulated upon stimuli. Until now, as new generation fluorescent tags (Eggeling et al., 2009) or most of the information on synaptic lipid composition comes modified toxins with specific lipid binding abilities such as the from the biochemical analysis of synaptosomal preparations. theta-toxin or lysenin, which bind cholesterol or sphingomyelin, Functional studies have also highlighted the relevant contri- respectively (Abe et al., 2012). These probes together with bution of certain lipids to spine physiology. From these two advanced microscopy techniques that achieve sub-diffraction types of approaches we now know that cholesterol and sphin- optical resolution (i.e., near-field scanning optical microscopy golipids are enriched in spines. Because of their chemical affinity (NSOM), photoactivated localization microscopy (PALM) these lipids form highly dynamic and heterogeneous membrane stochastic optical reconstruction microscopy (STORM) or nanodomains, the so called rafts, which can be stabilized to stimulated depletion (STED) fluorescent microscopy) allow the form larger platforms by protein-protein or protein-lipid inter- direct observation of the nanoscale dynamics of membrane lipids actions (Pike, 2006). Rafts compartmentalize cellular processes in a living cell (Eggeling et al., 2009; van Zanten et al., 2010; contributing to the accurate spatial and temporal organization Castro et al., 2013). As we gain insight on how lipids and their of molecules required at dendritic spines (Allen et al., 2007). Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 1 Dotti et al. Lipids in dendritic spines Neurotrophin and neurotransmitter receptors (NTRcs) are enriched in these structures (Hotulainen and Hoogenraad, 2010; recruited from extrasynaptic to synaptic sites through association Koleske, 2013). Changes in the amount of filamentous actin to lipid rafts, which reduce receptor lateral mobility at the synaptic (F-actin) mediate long-lasting alterations in spine size and synap- space (Nagappan and Lu, 2005; Fernandes et al., 2010). In fact, the tic efficacy. The repetitive firing of synapses that occurs dur- post synapse has been proposed as a lipid raft-enriched territory ing high-frequency stimulation to induce LTP, promotes actin and certain key structural proteins such as the postsynaptic den- polymerization and spine enlargement (Matsuzaki et al., 2004; sity protein 95 (PSD95) as well as AMPARc dynamically associate Okamoto et al., 2004). Conversely, treatment that weakens synap- to these domains (Perez and Bredt, 1998; Suzuki, 2002; Hering tic efficacy, such as low-frequency stimulation that results in et al., 2003; Suzuki et al., 2011). The tight control of the turnover LTD, causes F-actin loss and dendritic spine shrinkage (Okamoto of phosphoinositides and their derivatives plays also a central role et al., 2004; Zhou et al., 2004). Enlargement and shrinkage of in spine plasticity. We next describe data available on the presence the spine requires the coordination of the actin cytoskeleton of the aforementioned lipids in spines and on their contribution with the membrane. Recent work shows that the most abundant to spine physiology. Hopefully, the already mentioned imaging sphingolipid in neuronal membranes, sphingomyelin (SM), plays techniques based on advanced lipid probes and super-resolution a relevant role in the spine membrane-cytoskeleton crosstalk by microscopy together with most sensitive quantitative measure- modulating membrane binding and activity of main regulators ments (i.e., liquid chromatography coupled with tandem mass of the actin cytoskeleton at synapses: the Rho GTPases. Hence, spectrometry) would contribute to more precisely define the lipid high SM levels lower the amount of type I metabotropic gluta- composition of spines and its changes in real time in living cells. mate receptors (mGluRs) at the cell surface impairing membrane attachment, and therefore activity, of the small GTPase RhoA CHOLESTEROL concomitantly with the inhibition of its effectors ROCK and Profilin IIa. This seems to be the mechanism leading to reduced Pharmacological extraction of cholesterol or inhibition of its synthesis led to the disappearance of dendritic spines in cultured F-actin content and smaller size of spines in mice lacking the acid sphingomyelinase (ASM) gene (Arroyo et al., 2014). Conversely, hippocampal neurons, probably mediated by disruption of the actin cytoskeleton (Hering et al., 2003). This finding defined low SM levels in postsynaptic membranes are responsible for the enhanced activity of the RhoA-ROCK-Profilin I pathway resulting cholesterol as a core component of spines. A series of functional reports have demonstrated the relevance of this lipid for synaptic in increased actin polymerization and dendritic spine size in mice lacking the actin related protein WIP (Franco-Villanueva plasticity. Pioneer work showed that acute cyclodextrin-mediated removal of membrane cholesterol blocks LTP in the hippocampus et al., 2014). Moreover, the dynamic partitioning of RhoA into raft membrane domains, which is enhanced upon stimuli, is (Koudinov and Koudinova, 2001; Frank et al., 2008). On the other dependent on the maintenance of appropriate SM levels at the hand, excitatory neurotransmission, chronic and acute, induces cholesterol loss from synapses, which is recovered after stimuli synaptic membrane (Franco-Villanueva et al., 2014). Ceramide is another major sphingolipid contributing to spine (Sodero et al., 2011, 2012). In the aging brain, lifelong lasting synaptic activity and concomitant metabolic stress contributes to plasticity by virtue of its capacity to favor membrane fusogenicity promoting receptor clustering (Krönke, 1999). The rapid genera- a moderate but irreversible loss of membrane cholesterol (Sodero et al., 2011), which is thought to underlie cognitive deficits tion of ceramide modulates excitatory postsynaptic currents by controlling the insertion and clustering of NMDARc (Wheeler present at this stage of life (Martin et al., 2014). In agreement, cholesterol replenishment restores LTD in hippocampal slices et al., 2009). In agreement, direct additions of synthetic cell- permeable ceramide analogs increase excitatory postsynaptic cur- from aged mice and improves their learning and memory abilities (Martin et al., 2014). The molecular mechanisms by which rents without affecting presynaptic plasticity (Coogan et al., 1999; Fasano et al., 2003). The ceramide-associated enhancement of cholesterol influences postsynaptic plasticity are just beginning excitatory currents is often transient and is followed by sus- to be understood. Thus, impaired LTD in the old produced as tained depression of excitatory postsynaptic currents (Coogan consequence of lower membrane cholesterol can be explained, et al., 1999; Yang, 2000; Davis et al., 2006). These findings to a certain extent, by sustained activity of the PI3K/Akt pathway, in turn leading to inactivation of GSK3b and reduced support complex roles for the spatial and temporal produc- tion of ceramide in regulating neuronal excitability. In addition, AMPAR internalization (Martin et al., 2014). The broad effect of cholesterol on the biophysical properties of the membrane bilayer ceramide contributes to spine maturation by promoting the trans- formation of dendritic fillopodia into mature spines (Carrasco (i.e., viscosity, Renner et al., 2009) may affect the molecular flow in and out of synapses and therefore the mobility and interactions et al., 2012). of NTRc (Fantini and Barrantes, 2009). Changes in the amount of cholesterol at spines might also exert functional effects through PHOSPHOINOSITIDES AND DERIVATIVES cholesterol metabolites. Thus, the most abundant in the brain, Despite phosphoinositides (PIPs) are minor components of 24(S)-hydroxycholesterol, is a potent and selective positive synaptic membranes, their exceptional high rate of metabolic turnover and their compartmentalization make them key players modulator of NMDARc and enhances LTP (Paul et al., 2013). in postsynaptic excitability (Hammond and Schiavo, 2007). The SPHINGOLIPIDS presence at dendritic spines of the enzymes that interconvert Long term stability and dynamic changes in dendritic spines are different PIPs supports a relevant role for these lipids in the intimately linked to the actin cytoskeleton, which is particularly dynamics of these structures. Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 2 Dotti et al. Lipids in dendritic spines Continuous synthesis and availability of phosphatidylinosi- recruits and activates DAG effectors (among them PKC), which tol(3,4,5) triphosphate (PIP3) at the postsynaptic terminal is have been involved in spine maintenance (Brose et al., 2004). DAG necessary for sustaining synaptic function in rat hippocampal molecules are produced in dendritic spines through activation neurons (Arendt et al., 2010). PIP3 shows greater accumulation of postsynaptic receptors, including those of the NMDA type. in spines than in dendritic shafts under basal conditions. Inter- It has been proposed that the rapid and focal generation of estingly, glutamate stimulation promotes spine enlargement and DAG, together with ceramide, triggers the fusion of vesicles and the appearance of filopodia-like protrusions (spinules) projecting insertion of NMDARc subunits into lipid rafts. Based on the bio- from spines (Richards et al., 2005) to which PIP3 redistributes physical properties of DAG, it is likely that the generation of this (Ueda and Hayashi, 2013). Consistent with a key role for PIP3 lipid serves to destabilize the membranes to create fusion points at in spinule formation, blockage or inhibition of this lipid pre- the postsynapse (Wheeler et al., 2009). In turn, phosphatidic acid vent their appearance (Ueda and Hayashi, 2013). The biological (PA) that is generated by DAG phosphorylation, also regulates significance of spinules is not yet established. However, trans- spines together with its effectors. Among them, the alpha-p-21- endocytosis of these protrusions by presynaptic buttons may activated kinase PAK1 promotes spine formation by stabilizing aid postsynaptic membrane remodeling by removing the excess actin filaments through myosin phosphorylation (Zhang et al., membrane at postsynaptic sites (Spacek and Harris, 2004). It was 2005). also proposed that PIP3 signaling at spinules enables new synapses DYNAMISM OF THE LIPID COMPOSITION AT DENDRITIC to form with functional presynaptic boutons contributing to the change in synaptic connectivity. PIP3 could also mediate SPINES: THE ROLE OF LIPID METABOLIC ENZYMES membrane-cytoskeleton crosstalk at spines by virtue of its capac- The aforementioned evidences highlight not only the wealth and ity to regulate the activity of multiple Rho GTPase effectors (Yin specificity of the lipid composition at spines but also its dynamism and Janmey, 2003). Additionally, PIP3 is the upstream regulator and panoply of biological roles. The question remains on how of the Akt-mTOR pathway, which signals activity-dependent reg- this lipid composition is achieved and maintained, or changed, ulation of protein synthesis (Kelleher et al., 2004) and participates in different physiological situations. While still being an open in dendritic and spine morphogenesis (Kumar et al., 2005). question, local recruitment and removal of the different metabolic Appropriate levels and clustering of phosphatidylinositol(4,5) enzymes is a reasonable possibility. In fact, a number of these diphosphate (PIP2) at the postsynaptic membrane, which are enzymes have been localized in dendritic spines, change their modulated by the activities of Phospholipase g (PLCg) and activity upon synaptic stimuli and/or have the ability to modulate PIP5K, are important for synaptic plasticity, both LTP (Trovò NTRc trafficking and function. While the recruitment of certain et al., 2013) and LTD (Unoki et al., 2012). The PIP2-clustering enzymes occurs in response to stimuli others are constitutively molecule myristoylated alanine-rich C kinase substrate (MAR- present at postsynapses. In the following section we describe CKS) critically contributes to this requirement. The effector examples of the contribution of lipid metabolic enzymes to spine domain of MARCKS reversibly sequesters PIP2 on the plasma physiology. membrane, which can be released in response to local increases in intracellular calcium (McLaughlin and Murray, 2005). Low CHOLESTEROL 24-HYDROXYLASE levels of this protein, leading to PIP2 paucity at the mem- The cytochrome P450 enzyme, cholesterol 24-hydroxylase brane, promote the age-related impairment of synaptic plasticity (Cyp46A1) is selectively expressed in the brain, where it is (Figure 1). Hence, its overexpression in the hippocampus of old responsible for cholesterol oxidation and eventual excretion to mice or intraventricular perfusion of MARCKS peptide result in the general circulation (Lund et al., 1999). Pyramidal neurons enhanced LTP and improved memory (Trovò et al., 2013). On of the hippocampus and cortex, Purkinje cells of the cerebellum, the other hand, MARCKs appears to be a key molecule in spine and hippocampal and cerebellar interneurons show particularly morphogenesis promoting the transition from thin immature high levels of this enzyme, which is preferentially localized in dendritic spines to larger, more stable mushroom by controlling the endoplasmic reticulum (ER) of dendrites and cell bodies actin cytoskeleton (Calabrese and Halpain, 2005). In agreement, (Ramirez et al., 2008). Cyp46A1 contribution to synaptic plas- MARCKs deficient mice show impaired LTP and spatial cogni- ticity is supported by the observations that mice lacking this tion (McNamara et al., 1998; Hussain et al., 2006). Association enzyme present impaired learning and hippocampal LTP (Kotti of MARCKS to the membrane is necessary for its ability to et al., 2006) while mice overexpressing human Cyp46A1 present crosslink F-actin (Calabrese and Halpain, 2005). Membrane levels improved spatial memory (Maioli et al., 2013). Increased levels of of cholesterol, to which MARCKs can bind, would mediate this Cyp46A1 parallel the mild but significant cholesterol reduction in association. Evidence suggests that indeed defective MARCKs- membranes of the hippocampus of old rodents and of hippocam- induced PIP2 clustering in old synaptic membranes responds to pal neurons aged in culture (Martin et al., 2008; Sodero et al., the reduction of cholesterol levels during aging (Trovò et al., 2013; 2011). In turn, knockdown of the enzyme prevents glutamate- Martin et al., 2014; Figure 1). mediated cholesterol loss (Sodero et al., 2012), supporting a Besides PIPs themselves, PIP derived second messengers such cause-effect relationship between cholesterol reduction in the as Diacylglycerol (DAG) and 1,4,5-triphosphate (IP3) generated aged and Cyp46A1 increased activity. Biotinylation, electron by the hydrolysis of PIP2 by PLC, are also important in dendritic microscopy and TIRF analysis indicated that Cyp46A1 is present spine organization and function. Unlike IP3, which is released in spines of hippocampal neurons and that, upon stimulation, into the spine cytoplasm, DAG is embedded in the membrane and a close approximation occurs between the site of residence of Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 3 Dotti et al. Lipids in dendritic spines FIGURE 1 | Cholesterol regulation at spines upon glutamate stimulation. constitutive high intracellular calcium and irreversible cholesterol loss due to Acute glutamate stimulatory conditions lead to loss of membrane cholesterol. lifelong lasting synaptic activity leads to reduced membrane-associated The mechanism proposed involves glutamate induced rise in intracellular MARCKS, which affects synaptic plasticity by several mechanisms: (1) Ca++ leading to the approximation/apposition of ER membranes to the impaired MARCKS-mediated actin dynamics; (2) reduced membrane synaptic plasma membrane. This allows Cyp46A1, whose active site is in the clustering of PIP2; and (3) high PI3K activity resulting in reduced lumenal side of the ER, to oxidize cholesterol present in the exoplasmic glutamate-mediated Akt dephosphorylation and GSK3b activation. The later leaflet that is released as hydroxycholesterol. In the aging context, contributes to the impaired AMPARc internalization and LTD in aged neurons. the enzyme (the ER) and the plasma membrane, suggesting that enriched in hippocampus made it a likely candidate to modulate this could be the mechanism by which cholesterol is removed plasticity (Hofmann et al., 2000). In support, abundant NSM from the plasma membrane (Sodero et al., 2012). The increase has been found in synaptic membranes (Arroyo et al., 2014). in surface Cyp46A1 after stimulation supports this notion, and The rapid generation of ceramide by NSM modulates excitatory the higher production of its metabolite 24S-hydroxycholesterol postsynaptic currents by controlling the insertion and clustering in stimulated neurons indicates that the pool of the enzyme of NMDARc (Wheeler et al., 2009). In addition recent work shows that increase at the plasma membrane is active. Not surprisingly the ability of this enzyme to modulate spine actin cytoskeleton. for an ER-resident protein, the process of Cyp46A1 mediated Hence, activation of NSM corrects the abnormally low size and 2C cholesterol loss requires high levels of intracellular Ca and a F-actin content of dendritic spines in mice lacking the acid functional ER-plasma membrane communication via the stromal sphingomyelinase, which present high SM synaptic levels, by interaction molecule 2 (STIM2; Sodero et al., 2012). It has been enhancing the RhoA pathway (Arroyo et al., 2014). Conversely, 2C proposed that high levels of Ca elicit such communication NSM inhibition restores normal RhoA activity and diminishes bypassing the Golgi apparatus. This process would be consistent the abnormally increased size and F-actin levels of spines in with the observation that the distance between the ER and the neurons of mice lacking WIP (Franco-Villanueva et al., 2014; plasma membrane can be as small as 10 nm (Pichler et al., Figure 2). This actin-related protein has the ability to sense the 2001; Lebiedzinska et al., 2009) and that NMDARc stimula- levels of F-actin to which it can bind. It has been proposed that tion produces a transient and reversible fission of ER tubules WIP modulates SM amount at the spine membrane by RhoA (Kucharz et al., 2009). This mechanism provides an efficient, mediated transcriptional control of the NSM, thus controlling temporally and spatially controlled, mean to change postsynaptic the spine response to actin polymerization stimuli (Franco- membrane lipid composition (Figure 1). Whether lipid metabolic Villanueva et al., 2014). This places NSM at a key position to enzymes other than Cyp46A1 follow the same mechanism is mediate membrane-cytoskeleton crosstalk at spines. It remains unknown. to be determined whether the enzyme levels and activity could be modulated at synapses by a local transcriptional control NEUTRAL SPHINGOMYELINASE-2 mechanism. The observation that activation of NSM with Among the sphingolipid metabolic enzymes the Neutral dexamethasone corrects actin related anomalies in isolated sphingomeylinase-2 (NSM) has been directly related to spine synaptosomes argues in favor of this possibility (Arroyo et al., size and to postsynaptic function. NSM is the main responsible 2014). If true, the question arises on whether, similar to those of SM degradation and conversion to ceramide at the plasma of many actin related proteins, mRNAs of lipid metabolic membrane (Stoffel, 1999). Its rapid kinetics and location enzymes are present at synapses to facilitate the immediate spine Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 4 Dotti et al. Lipids in dendritic spines FIGURE 2 | SM and its catabolic enzymes in dendritic spine physiology binding and pathway activation, which diminish spine F-actin content and size. and pathology. SM levels at the postsynaptic membrane modulate These anomalies can be corrected by NSM activation. Conversely, mice membrane binding and activation of the small GTPase RhoA, which in turn lacking the actin related protein WIP show constitutively active NSM leading modulates F-actin content through its effectors ROCK and profillin 2A. This to reduced SM levels, which enhance RhoA membrane binding and pathway molecular mechanism controls dendritic spine size. The SM catabolic activation resulting in bigger dendritic spines with higher F-actin content. enzymes ASM and NSM are involved in this process. Hence, mice lacking Spine anomalies could explain the cognitive deficits observed in ASMko mice, ASM show abnormally high SM levels in their postsynaptic membranes that which are a model for Niemann Pick disease type A, and those of individuals lower the amount of cell surface mGluRs. This impairs RhoA membrane carrying mutations in the region encoding for WIP. remodeling in response to stimuli. Alternatively, NSM would Instead, CPT1C may influence the generation of ceramide from translocate to the synaptic plasma membrane upon stimulation. the sphingosine pool through the salvage pathway and/or on its This is supported by evidences in non-neuronal cells showing degradation. CPT1C deficiency increases immature filopodia and that a stress-mediated PKC mechanism induces the appearance reduces mature mushroom and stubby spines, while not affecting of the enzyme at the plasma membrane (Clarke et al., 2008). total spine number or spine head area. These effects on spine The possibility that not only NSM but also its analog enzyme, maturation can be restored by ceramide addition (Carrasco et al., ASM, regulates SM levels at the postsynaptic membrane is not yet 2012). Consistent with the role of CPT1C on the transforma- clarified. The presence of ASM in spines has not been reported. tion of dendritic filopodia into mature spines, mice lacking this However, the observations that lack of this enzyme leads to enzyme show defects in hippocampus dependent learning abilities reduced spine size and F-actin content (Arroyo et al., 2014) and (Carrasco et al., 2012). that it can function at neutral pH (Schissel et al., 1998) or in PHOSPHOINOSITIDE METABOLIC ENZYMES acidified microenvironments that may exist at the cell surface Several enzymes tightly control PIP turnover at dendritic spines (Bourguignon et al., 2004), support the regulated action of the (Figure 3). Biochemical and imaging experiments demonstrated two sphingomyelinases to control spine SM levels and actin that the phosphatase and tensin homolog deleted on chromosome cytoskeleton (Figure 2). ten (PTEN), which converts PIP3 into PIP2 (Maehama and CARNITINE PALMITOYLTRANSFERASE 1C (CPT1C) Dixon, 1999), is recruited to dendritic spines upon NMDARc The brain specific isoform of Carnitine Palmitoyltransferase 1 but not AMPARc activation (Jurado et al., 2010). NMDARc (CPT1C), modulates ceramide levels in hippocampal neurons activation triggers a biphasic regulation of PTEN mobility in where it is especially enriched (Carrasco et al., 2012). CPT1C is dendritic spines. First, there is a rapid and transient increase located in the ER and has been recently found inside dendritic in mobility independent from PTEN interactions through its spines. The mechanism by which this enzyme, which facilitates PDZ motif. A longer-lasting and PDZ-dependent anchoring of fatty acid transport across intracellular membranes (Wolfgang PTEN to the postsynaptic density follows this phase. This reg- et al., 2006), modulates ceramide levels is still unknown. Acti- ulated mechanism of recruitment of PTEN may provide means vation of de novo synthesis of the lipid has been discarded. to achieve synapse-specific modulation of PIP3 signaling during Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 5 Dotti et al. Lipids in dendritic spines of synaptic stimuli. It has been proposed that lipid signals (i.e., 2-arachidonoylglycerol) generated at dendritic spines by PLC activity, upon activation of type I metabotropic glutamate receptors (mGluRs), diffuse across the synaptic cleft and activate 2C cannabinoid receptors, reducing presynpatic Ca channel activ- ity and inhibiting further glutamate release (Chevaleyre et al., 2006). DAG KINASES Evidence accumulates in support of the notion that DAG- metabolizing enzymes DAG kinases (DGK), which are coupled to synaptic scaffolding proteins, tightly control synaptic DAG concentrations (Kim et al., 2010). Activation of NTRc, including mGluR and NMDARc, induce the production of DAG and its phosphorylation by DGKs, converting DAG into PA. The DGKz isoform has been critically involved in spine maintenance. DGKz is targeted to excitatory synapses through its direct interaction with the postsynaptic scaffold protein PSD-95. Overexpression of DGKz in cultured neurons increases the number of dendritic spines in a manner requiring its catalytic activity and PSD- FIGURE 3 | PIP metabolism in spine plasticity. Activation of NMDARc 95 binding. Conversely, DGKz knockdown reduces spine den- modulate AMPARc trafficking through spatially and timely controlled activity of PIPs and their metabolic enzymes. On one hand, PI3K association with sity (Kim et al., 2009). In agreement, mice deficient in DGKz AMPARc is required for receptor cell surface delivery during LTP. On the expression show reduced spine density and excitatory synaptic other hand, PTEN activity leading to PIP3 downregulation promotes transmission. Time-lapse imaging indicates that DGKz is required migration of AMPARc from the postsynaptic density to the perisynaptic for spine maintenance but not formation (Kim et al., 2009). It has membrane. This depresses AMPARc synaptic responses by promoting been proposed that DAG and PA signaling pathways are integrated receptor endocytosis during LTD. Moreover, signaling pathways initiated by PIP3 or PIP2, in which Akt/mTOR, DAG and IP3 are involved, contribute to within synaptic multi-protein complexes that intersect with small actin remodeling and spine changes in size. GTPases controlling actin cytoskeleton (Tada and Sheng, 2006; Kim et al., 2010). INFLUENCE OF MEMBRANE LIPIDS ON GLUTAMATE plasticity. The enhancement of PTEN lipid phosphatase activ- RECEPTOR FUNCTION AT DENDRITIC SPINES ity is able to drive depression of AMPARc-mediated synaptic responses (Jurado et al., 2010). Consistently, mice with altered Modifications in the number and complement of glutamate- PTEN expression show multiple impairments in synaptic func- sensing receptors in the postsynaptic membrane are key mech- tion including LTP and LTD (Wang et al., 2006; Fraser et al., anisms to adjust strength in excitatory synapses. AMPA and 2008). NMDA-type glutamate receptors are ligand-gated ion chan- The class I phosphatydilinsositol-3-kinase (PI3K) constitu- nels critical for synaptic plasticity (Barria and Malinow, 2002; tively localizes at synapses by means of a direct interaction Malinow and Malenka, 2002; Washbourne et al., 2004). Although between its p85 subunit and the AMPARc (Man et al., 2003). By the identification and characterization of proteins involved in converting PIP2 into PIP3 this kinase ensures the delivery of new the regulation of these receptors has been a productive area AMPARc into spines in response to NMDARc activation (Man of research, there has been less progress in understanding how et al., 2003) and the maintenance of AMPARc clustering at the changes in membrane lipids affect their function. Lipids could postsynaptic membrane (Arendt et al., 2010; Figure 3). modulate glutamate receptor affinity or capacity to bind their lig- The major PIP2 producing enzyme in the brain, the ands by influencing receptor conformation, orientation, subunit phosphatidylinositol-4-phosphate 5-kinaseg661 (PIP5Kg661), composition or oligomerization. Lipids could as well alter the becomes dephosphorylated and associates with the clathrin adap- properties of the channels themselves. Lateral movement and tor protein complex AP-2 at postsynapses upon NMDA receptor endo-exocytic trafficking of NTRcs are essential for glutamate activation (Unoki et al., 2012). This event is necessary to elicit signaling. Lipids are also good candidates to regulate these mem- AMPARc endocytosis and LTD. PLC, which catalyzes hydrolysis brane dependent events. Although we still lack accurate informa- of PIP2, is enriched in spine heads and primarily localized in tion about the differences in lipid composition between synaptic a thin border around the postsynaptic density (Yoshida et al., and extrasynaptic sites, specific lipid changes (i.e., cholesterol 2006). PLC activity is enhanced by NMDARc stimulation and or PIP3 loss) affect the synaptic but not the extrasynaptic pool its blockage impairs LTD (Reyes-Harde and Stanton, 1998). This of AMPARc (Arendt et al., 2010; Martin et al., 2014). Hence, activity is required for changes in postsynaptic structure by lipids could contribute to the balance between synaptic and depolymerizing spine actin and decreasing PSD95 levels. This in extrasynaptic glutamate receptor activity, which is key for synaptic turn promotes AMPARc internalization during LTD (Horne and plasticity. Accumulating evidence supports the view that lipid Dell’Acqua, 2007). PLC has been also related to the termination rafts provide both a spatial and a temporal meeting point for Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 6 Dotti et al. Lipids in dendritic spines receptors and proteins involved in a common pathway facilitating Different studies indicate that AMPARc trafficking depends on their intracellular signaling (Allen et al., 2007). Supporting the PIP metabolism (Figure 3). Direct association of AMPARc with relevance of rafts for glutamate receptor function, different sub- PI3K is required for receptor cell surface insertion and expression units of NMDARc (GluN1A, GluN2A, GluN2B) and AMPARc during LTP (Man et al., 2003). It has been proposed that the (GluA1, 2/3 and 4) have been localized to these membrane mobility of synaptic but not extra-synaptic AMPA receptors dur- domains (Hering et al., 2003; Allen et al., 2007). Because of their ing LTD requires PIP3 depletion (Arendt et al., 2010). Hence, localization in spines and importance for postsynaptic excitatory down-regulation of PIP3, either by overexpression of its pleckstrin transmission we will next comment examples of particular lipids homology (PH) domain or by inhibiting PI3K, impairs PSD-95 influencing AMPARc and NMDARc function. accumulation in spines and promotes AMPARc mobility leading to their migration from the postsynaptic density, where excitatory LIPID INFLUENCE ON AMPARc transmission occurs, towards the perisynaptic membrane within the spine, enabling synaptic depression (Arendt et al., 2010). PIP3 AMPARc mediate most excitatory transmission in the brain, and their regulated addition and removal from the postsynaptic effects are specific for synaptic AMPARc, since it does not affect NMDARc nor extrasynaptic AMPARc. Given PIP3 contribution membrane leads to long lasting forms of synaptic plasticity such as LTP and LTD (Malinow and Malenka, 2002). In addition, to the accumulation of PSD95 at spines, it has been proposed that the lipid favors AMPARc retention via modulation of the PSD95 AMPARc continuously cycle in and out the synaptic membrane independently of synaptic activity. This constitutive trafficking synaptic scaffold. Complementary, enhancement of PTEN lipid involves both exocytic delivery from intracellular compartments phosphatase activity, which turns PIP3 into PIP2, is able to drive depression of AMPA receptor-mediated synaptic responses. This (Gerges et al., 2006), fast exchange with surface extra-synaptic receptors via lateral diffusion (Tardin et al., 2003) and internaliza- activity is specifically required for NMDARc-dependent LTD but not for LTP or mGluR-dependent LTD (Jurado et al., 2010). Fur- tion of the displaced receptors by endocytosis, which is essential to sustain LTD (Carroll et al., 1999; Beattie et al., 2000). Although ther turnover of PIP2 by PLC favors synaptic actin depolymeriza- tion and PSD95 degradation, also contributing to the reduction for most of these effects the specific molecular mechanism has not yet been elucidated, experimental modulation of lipids in brain of surface AMPARc expression and spine remodeling (Horne and Dell’Acqua, 2007). slices or cultured neurons lead to changes in AMPARc localization and electrophysiological behavior. As we next describe, some of LIPID INFLUENCE ON NMDARc these effects received in vivo confirmation in mouse models with genetically or experimentally altered lipid content. NMDARc are heterotetrameric ion channels directly implicated Cholesterol depletion reduces early-AMPA-mediated calcium in LTP and LTD being the predominant molecular device for influx (Frank et al., 2008). It was proposed that this effect was controlling synaptic plasticity and memory function (Bashir et al., not due to a direct influence on the AMPARc channel kinetics 1991; Cui et al., 2004; Li and Tsien, 2009). Studies performed but to altered surface expression of at least a subpopulation of with purified NMDARc reconstituted in liposomes showed that 2C AMPARc. Indeed, cholesterol levels have been shown to modulate membrane stretch reduce Mg blockade of NMDA channel AMPARc surface mobility (Renner et al., 2009) as well as endo- enhancing ion currents (Kloda et al., 2007). As these results were somal dynamics (Hering et al., 2003; Hou et al., 2008). The loss obtained in a minimal system that lacks cellular proteins, they of cholesterol in synaptic membranes of aged neurons impairs unambiguously demonstrate that mechanical deformation of the AMPARc internalization due to PI3K/Akt activation, which pre- lipid bilayer is sufficient to modulate the gating properties of cludes Akt dephosphorylation required for GSK3b activation- NMDA channels (Piomelli et al., 2007). Experimental evidence mediated glutamate receptor endocytosis (Martin et al., 2014). suggests that as much as 60% of NMDARc are located in lipid rafts Quantum-dot-based single molecule tracking analysis showed (Besshoh et al., 2005), which by virtue of their particular physical that reduction of cholesterol also affects GluR2-AMPARc lateral properties might dynamically regulate NMDARc subunit compo- diffusion. These alterations lead to the impaired LTD typical of sition and trafficking. In support of this possibility, changes in old neurons. Consistently, increasing cholesterol levels in vitro or cholesterol content inhibit NMDA-stimulated influx of calcium in vivo by chronic infusion of the lipid restores LTD and cognitive in hippocampal cells in culture (Frank et al., 2004). Cholesterol deficits in the old mice (Martin et al., 2014). reduction redistributes the NMDARc GluN2B subunit, from rafts Little is known about the influence of membrane shingolipids to non-raft membrane fractions (Abulrob et al., 2005). On the in AMPARc function. A positive role for the signaling sph- other hand, the cholesterol metabolite 24(S)-hydroxycholesterol ingolipid Sphingosine-1-phosphate (S1P) in AMPARc-mediated has been recently identified as a potent and highly selective miniature excitatory postsynaptic currents has been reported positive modulator of NMDARc. This hydroxysterol enhances in hippocampal slices. Inhibition of sphingosine kinase (SphK) NMDARc currents and LTP and restores behavioral and cogni- impaired LTP that was fully restored by S1P addition. Con- tive deficits in rodents treated with NMDARc channel blockers sistently, mice lacking SphK show poor memory performance (Paul et al., 2013). It appears that the mechanism underlying (Kanno et al., 2010). However, it has been proposed that these these effects does not involve receptor insertion or transcrip- effects do not take place in spines but correlate with the S1P- tion but direct binding of the lipid to a modulatory site in the induced translocation of S1P receptors to presynaptic terminals receptor. thereby facilitating S1P receptor-mediated signals towards gluta- Dysregulation of brain sphingolipid balance following inhibi- mate release. tion of NSM alters the subunit composition of NMDARc that Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 7 Dotti et al. Lipids in dendritic spines might account for memory impairment following long-term ACKNOWLEDGMENTS inhibition of NSM (Tabatadze et al., 2010). NSM activity mod- The authors thank the support of the Ministerio Español de ulates the phosphorylation of the NMDARc subunit GluN1 on Ciencia e Innovacion (SAF2011-24550 to María Dolores Ledesma, serine 896 promoting the clustering of these modified subunits SAF2013-45392-R to Carlos Gerardo Dotti, SAF2011-24730 to into lipid rafts. It has been proposed that the rapid and focal gen- Jose Antonio Esteban, and Consolider Grant CSD2010-00045 to eration of ceramide upon NSM activation shifts the composition Carlos Gerardo Dotti, María Dolores Ledesma and Jose Antonio of membrane lipids to bring into close proximity GluN1 and its Esteban). kinases PKC and PKA (Wheeler et al., 2009). 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Morphological changes in dendritic spines 2014. associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071– Citation: Dotti CG, Esteban JA and Ledesma MD (2014) Lipid dynamics at dendritic 1089. doi: 10.1146/annurev.neuro.24.1.1071 spines. Front. Neuroanat. 8:76. doi: 10.3389/fnana.2014.00076 Zhang, H., Webb, D. J., Asmussen, H., Niu, S., and Horwitz, A. F. (2005). This article was submitted to the journal Frontiers in Neuroanatomy. A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and Copyright © 2014 Dotti, Esteban and Ledesma. This is an open-access article dis- synapse formation through MLC. J. Neurosci. 25, 3379–3388. doi: 10.1523/ tributed under the terms of the Creative Commons Attribution License (CC BY). jneurosci.3553-04.2005 The use, distribution or reproduction in other forums is permitted, provided the Zhou, Q., Homma, K. J., and Poo, M. M. (2004). Shrinkage of dendritic spines original author(s) or licensor are credited and that the original publication in this associated with long-term depression of hippocampal synapses. Neuron 44, 749– journal is cited, in accordance with accepted academic practice. No use, distribution 757. doi: 10.1016/j.neuron.2004.11.011 or reproduction is permitted which does not comply with these terms. Frontiers in Neuroanatomy www.frontiersin.org August 2014 | Volume 8 | Article 76 | 11

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