Limits...
Lipid dynamics at dendritic spines.

Dotti CG, Esteban JA, Ledesma MD - Front Neuroanat (2014)

Bottom Line: However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants.Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling.We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

View Article: PubMed Central - PubMed

Affiliation: Centro Biología Molecular Severo Ochoa, CSIC-UAM Madrid, Spain.

ABSTRACT
Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling. In this review we gather information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

No MeSH data available.


Related in: MedlinePlus

SM and its catabolic enzymes in dendritic spine physiology and pathology. SM levels at the postsynaptic membrane modulate membrane binding and activation of the small GTPase RhoA, which in turn modulates F-actin content through its effectors ROCK and profillin 2A. This molecular mechanism controls dendritic spine size. The SM catabolic enzymes ASM and NSM are involved in this process. Hence, mice lacking ASM show abnormally high SM levels in their postsynaptic membranes that lower the amount of cell surface mGluRs. This impairs RhoA membrane binding and pathway activation, which diminish spine F-actin content and size. These anomalies can be corrected by NSM activation. Conversely, mice lacking the actin related protein WIP show constitutively active NSM leading to reduced SM levels, which enhance RhoA membrane binding and pathway activation resulting in bigger dendritic spines with higher F-actin content. Spine anomalies could explain the cognitive deficits observed in ASMko mice, which are a model for Niemann Pick disease type A, and those of individuals carrying mutations in the region encoding for WIP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126552&req=5

Figure 2: SM and its catabolic enzymes in dendritic spine physiology and pathology. SM levels at the postsynaptic membrane modulate membrane binding and activation of the small GTPase RhoA, which in turn modulates F-actin content through its effectors ROCK and profillin 2A. This molecular mechanism controls dendritic spine size. The SM catabolic enzymes ASM and NSM are involved in this process. Hence, mice lacking ASM show abnormally high SM levels in their postsynaptic membranes that lower the amount of cell surface mGluRs. This impairs RhoA membrane binding and pathway activation, which diminish spine F-actin content and size. These anomalies can be corrected by NSM activation. Conversely, mice lacking the actin related protein WIP show constitutively active NSM leading to reduced SM levels, which enhance RhoA membrane binding and pathway activation resulting in bigger dendritic spines with higher F-actin content. Spine anomalies could explain the cognitive deficits observed in ASMko mice, which are a model for Niemann Pick disease type A, and those of individuals carrying mutations in the region encoding for WIP.

Mentions: Among the sphingolipid metabolic enzymes the Neutral sphingomeylinase-2 (NSM) has been directly related to spine size and to postsynaptic function. NSM is the main responsible of SM degradation and conversion to ceramide at the plasma membrane (Stoffel, 1999). Its rapid kinetics and location enriched in hippocampus made it a likely candidate to modulate plasticity (Hofmann et al., 2000). In support, abundant NSM has been found in synaptic membranes (Arroyo et al., 2014). The rapid generation of ceramide by NSM modulates excitatory postsynaptic currents by controlling the insertion and clustering of NMDARc (Wheeler et al., 2009). In addition recent work shows the ability of this enzyme to modulate spine actin cytoskeleton. Hence, activation of NSM corrects the abnormally low size and F-actin content of dendritic spines in mice lacking the acid sphingomyelinase, which present high SM synaptic levels, by enhancing the RhoA pathway (Arroyo et al., 2014). Conversely, NSM inhibition restores normal RhoA activity and diminishes the abnormally increased size and F-actin levels of spines in neurons of mice lacking WIP (Franco-Villanueva et al., 2014; Figure 2). This actin-related protein has the ability to sense the levels of F-actin to which it can bind. It has been proposed that WIP modulates SM amount at the spine membrane by RhoA mediated transcriptional control of the NSM, thus controlling the spine response to actin polymerization stimuli (Franco-Villanueva et al., 2014). This places NSM at a key position to mediate membrane-cytoskeleton crosstalk at spines. It remains to be determined whether the enzyme levels and activity could be modulated at synapses by a local transcriptional control mechanism. The observation that activation of NSM with dexamethasone corrects actin related anomalies in isolated synaptosomes argues in favor of this possibility (Arroyo et al., 2014). If true, the question arises on whether, similar to those of many actin related proteins, mRNAs of lipid metabolic enzymes are present at synapses to facilitate the immediate spine remodeling in response to stimuli. Alternatively, NSM would translocate to the synaptic plasma membrane upon stimulation. This is supported by evidences in non-neuronal cells showing that a stress-mediated PKC mechanism induces the appearance of the enzyme at the plasma membrane (Clarke et al., 2008). The possibility that not only NSM but also its analog enzyme, ASM, regulates SM levels at the postsynaptic membrane is not yet clarified. The presence of ASM in spines has not been reported. However, the observations that lack of this enzyme leads to reduced spine size and F-actin content (Arroyo et al., 2014) and that it can function at neutral pH (Schissel et al., 1998) or in acidified microenvironments that may exist at the cell surface (Bourguignon et al., 2004), support the regulated action of the two sphingomyelinases to control spine SM levels and actin cytoskeleton (Figure 2).


Lipid dynamics at dendritic spines.

Dotti CG, Esteban JA, Ledesma MD - Front Neuroanat (2014)

SM and its catabolic enzymes in dendritic spine physiology and pathology. SM levels at the postsynaptic membrane modulate membrane binding and activation of the small GTPase RhoA, which in turn modulates F-actin content through its effectors ROCK and profillin 2A. This molecular mechanism controls dendritic spine size. The SM catabolic enzymes ASM and NSM are involved in this process. Hence, mice lacking ASM show abnormally high SM levels in their postsynaptic membranes that lower the amount of cell surface mGluRs. This impairs RhoA membrane binding and pathway activation, which diminish spine F-actin content and size. These anomalies can be corrected by NSM activation. Conversely, mice lacking the actin related protein WIP show constitutively active NSM leading to reduced SM levels, which enhance RhoA membrane binding and pathway activation resulting in bigger dendritic spines with higher F-actin content. Spine anomalies could explain the cognitive deficits observed in ASMko mice, which are a model for Niemann Pick disease type A, and those of individuals carrying mutations in the region encoding for WIP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126552&req=5

Figure 2: SM and its catabolic enzymes in dendritic spine physiology and pathology. SM levels at the postsynaptic membrane modulate membrane binding and activation of the small GTPase RhoA, which in turn modulates F-actin content through its effectors ROCK and profillin 2A. This molecular mechanism controls dendritic spine size. The SM catabolic enzymes ASM and NSM are involved in this process. Hence, mice lacking ASM show abnormally high SM levels in their postsynaptic membranes that lower the amount of cell surface mGluRs. This impairs RhoA membrane binding and pathway activation, which diminish spine F-actin content and size. These anomalies can be corrected by NSM activation. Conversely, mice lacking the actin related protein WIP show constitutively active NSM leading to reduced SM levels, which enhance RhoA membrane binding and pathway activation resulting in bigger dendritic spines with higher F-actin content. Spine anomalies could explain the cognitive deficits observed in ASMko mice, which are a model for Niemann Pick disease type A, and those of individuals carrying mutations in the region encoding for WIP.
Mentions: Among the sphingolipid metabolic enzymes the Neutral sphingomeylinase-2 (NSM) has been directly related to spine size and to postsynaptic function. NSM is the main responsible of SM degradation and conversion to ceramide at the plasma membrane (Stoffel, 1999). Its rapid kinetics and location enriched in hippocampus made it a likely candidate to modulate plasticity (Hofmann et al., 2000). In support, abundant NSM has been found in synaptic membranes (Arroyo et al., 2014). The rapid generation of ceramide by NSM modulates excitatory postsynaptic currents by controlling the insertion and clustering of NMDARc (Wheeler et al., 2009). In addition recent work shows the ability of this enzyme to modulate spine actin cytoskeleton. Hence, activation of NSM corrects the abnormally low size and F-actin content of dendritic spines in mice lacking the acid sphingomyelinase, which present high SM synaptic levels, by enhancing the RhoA pathway (Arroyo et al., 2014). Conversely, NSM inhibition restores normal RhoA activity and diminishes the abnormally increased size and F-actin levels of spines in neurons of mice lacking WIP (Franco-Villanueva et al., 2014; Figure 2). This actin-related protein has the ability to sense the levels of F-actin to which it can bind. It has been proposed that WIP modulates SM amount at the spine membrane by RhoA mediated transcriptional control of the NSM, thus controlling the spine response to actin polymerization stimuli (Franco-Villanueva et al., 2014). This places NSM at a key position to mediate membrane-cytoskeleton crosstalk at spines. It remains to be determined whether the enzyme levels and activity could be modulated at synapses by a local transcriptional control mechanism. The observation that activation of NSM with dexamethasone corrects actin related anomalies in isolated synaptosomes argues in favor of this possibility (Arroyo et al., 2014). If true, the question arises on whether, similar to those of many actin related proteins, mRNAs of lipid metabolic enzymes are present at synapses to facilitate the immediate spine remodeling in response to stimuli. Alternatively, NSM would translocate to the synaptic plasma membrane upon stimulation. This is supported by evidences in non-neuronal cells showing that a stress-mediated PKC mechanism induces the appearance of the enzyme at the plasma membrane (Clarke et al., 2008). The possibility that not only NSM but also its analog enzyme, ASM, regulates SM levels at the postsynaptic membrane is not yet clarified. The presence of ASM in spines has not been reported. However, the observations that lack of this enzyme leads to reduced spine size and F-actin content (Arroyo et al., 2014) and that it can function at neutral pH (Schissel et al., 1998) or in acidified microenvironments that may exist at the cell surface (Bourguignon et al., 2004), support the regulated action of the two sphingomyelinases to control spine SM levels and actin cytoskeleton (Figure 2).

Bottom Line: However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants.Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling.We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

View Article: PubMed Central - PubMed

Affiliation: Centro Biología Molecular Severo Ochoa, CSIC-UAM Madrid, Spain.

ABSTRACT
Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling. In this review we gather information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

No MeSH data available.


Related in: MedlinePlus