Lipid dynamics at dendritic spines

We probably need dendritic branching to recover. What is your doctor doing to accomplish that? Look at the last bolded sentence, this is what makes me think cholesterol reduction is not necessarily good for our recovery. But I'm stupid because I'm not medically trained and thus should never be listened to.
http://journal.frontiersin.org/Journal/10.3389/fnana.2014.00076/full?

Carlos Gerardo Dotti^*, Jose Antonio Esteban and María Dolores Ledesma^*

• Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain

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.

Introduction

At most excitatory synapses in the Central Nervous System, presynaptic boutons synapse onto small membrane protrusions that emerge from the dendritic shaft: the dendritic spines. Changes in dendritic spine number, size and shape contribute to determine the strength of excitatory synaptic transmission (Yuste and Bonhoeffer, 2001; Carlisle and Kennedy, 2005). The remodeling of these membrane protrusions in response to stimuli depends on lipids, which are major components of the membrane with the ability to shape it and modify protein activities within. However, only recently the contribution of spine lipids has attracted similar attention to that of spine proteins. Pioneer work showing the requirement of glial cholesterol for synapse formation (Mauch et al., 2001) and the elimination of spines upon reduction of cholesterol or sphingolipids (Hering et al., 2003) triggered research in this field. Technical progress facilitates today the not so long ago impossible analysis of the subtle changes in lipid composition and of the topographical distribution of individual lipid species in cellular compartments. Probes have been developed to label lipid molecules such as new generation fluorescent tags (Eggeling et al., 2009) or modified toxins with specific lipid binding abilities such as the theta-toxin or lysenin, which bind cholesterol or sphingomyelin, respectively (Abe et al., 2012). These probes together with advanced microscopy techniques that achieve sub-diffraction optical resolution (i.e., near-field scanning optical microscopy (NSOM), photoactivated localization microscopy (PALM) stochastic optical reconstruction microscopy (STORM) or stimulated depletion (STED) fluorescent microscopy) allow the direct observation of the nanoscale dynamics of membrane lipids in a living cell (Eggeling et al., 2009; van Zanten et al., 2010; Castro et al., 2013). As we gain insight on how lipids and their metabolic enzymes regulate dendritic spine shape and protein function their importance is confirmed and strengthened. We aim here to review this knowledge focusing the attention on the dynamic lipidomics of dendritic spines. We will also discuss about how this influences synaptic plasticity through the modulation of glutamate receptors of the AMPA and NMDA-type (AMPARc and NMDARc). These receptors are instrumental to elicit Long Term Potentiation (LTP) and Long Term Depression (LTD), which are considered the molecular mechanisms underlying learning and memory (Neves et al., 2008; Collingridge et al., 2010).

Lipid Composition at Dendritic Spines

A relevant question about spine physiology is whether spine membrane lipid composition and organization is different to that of the dendritic shaft membranes from which these protrusions emerge. A systematic analysis of spine lipid composition is lacking due to technical limitations. However, accumulating evidence indicates it differs from that of the shaft. This raises questions such as why this specificity is necessary and how it is achieved, maintained or modulated upon stimuli. Until now, most of the information on synaptic lipid composition comes from the biochemical analysis of synaptosomal preparations. Functional studies have also highlighted the relevant contribution of certain lipids to spine physiology. From these two types of approaches we now know that cholesterol and sphingolipids are enriched in spines. Because of their chemical affinity these lipids form highly dynamic and heterogeneous membrane nanodomains, the so called rafts, which can be stabilized to form larger platforms by protein-protein or protein-lipid interactions (Pike, 2006). Rafts compartmentalize cellular processes contributing to the accurate spatial and temporal organization of molecules required at dendritic spines (Allen et al., 2007). Neurotrophin and neurotransmitter receptors (NTRcs) are recruited from extrasynaptic to synaptic sites through association to lipid rafts, which reduce receptor lateral mobility at the synaptic space (Nagappan and Lu, 2005; Fernandes et al., 2010). In fact, the post synapse has been proposed as a lipid raft-enriched territory and certain key structural proteins such as the postsynaptic density protein 95 (PSD95) as well as AMPARc dynamically associate to these domains (Perez and Bredt, 1998; Suzuki, 2002; Hering et al., 2003; Suzuki et al., 2011). The tight control of the turnover of phosphoinositides and their derivatives plays also a central role in spine plasticity. We next describe data available on the presence of the aforementioned lipids in spines and on their contribution to spine physiology. Hopefully, the already mentioned imaging techniques based on advanced lipid probes and super-resolution microscopy together with most sensitive quantitative measurements (i.e., liquid chromatography coupled with tandem mass spectrometry) would contribute to more precisely define the lipid composition of spines and its changes in real time in living cells.

Cholesterol

Pharmacological extraction of cholesterol or inhibition of its synthesis led to the disappearance of dendritic spines in cultured hippocampal neurons, probably mediated by disruption of the actin cytoskeleton (Hering et al., 2003). This finding defined cholesterol as a core component of spines.

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