Endoplasmic reticulum function in dendrites and dendritic spines of hippocampal neurons

Sammanfattning: In the hippocampus, dendritic spines are compartmentalized postsynaptic micro-domains in the excitatory synapse. Subsets of bigger and mushroom-shaped hippocampal dendritic spines contain tubules and cisterns of endoplasmic reticulum (ER) that are connected to the soma and dendrites of the neuron. These ER containing spines differ in their ability to retain ER. We hypothesized a functional coupling of the ER to the plasma membrane (PM) via protein-protein interaction at specialized junctions, which we believe to anchor ER within spines. Although the molecular composition of such an ER-plasma membrane junction (ERPMJ) is yet to be elucidated, we showed that a subset of ERPMJs containing type I transmembrane proteins sensitive to phorbol ester induced metalloproteinase and subsequent gamma-secretase mediated remodelling, and that these proteins may be involved in regulating spine ER dynamics. The gamma-secretase is a multimeric complex with presenilin protein as the catalytic component. Findings have implicated mutations in the presenilin genes clinically associated to familial Alzheimer’s disease (FAD) with altered store-operated calcium entry (SOCE) response. SOCE is a cellular homeostatic mechanism that is activated to restore the depleted ER calcium store via specialized store-operated calcium channels (SOC) localized in the PM. With SOCE-inducing protein STIM1, we explored the effect of a FAD M146V mutation in presenilin-1 (PS1) on spine ER dynamics as well as on STIM1 function. In EGFP-STIM1-expressing hippocampal neurons established from wild-type and FAD PS1 mutant mice, we used 3,5-dihydroxyphenylglycine (DHPG) and carbachol, agonist of type I metabotropic glutamate receptors and muscarinic acetylcholine receptors to trigger calcium release from the ER via IP3R. Surprisingly, STIM1 activation appeared not to be affected by the PS1-M146V mutation although SOCE was impaired. Separately, we showed that DHPG or carbachol stimulation in PS1-M146V neurons led to a significant ER loss from spines that was exclusively mediated by mechanisms controlling ER entry into spines. We hypothesized that the PS1-M146V mutation altered yet to be elucidated mechanisms regulating ER entry into spines, and which may well contribute to synaptic dysfunction in FAD. Looking forward, there is value in future research to elucidate novel molecules and signaling pathways vis-a-vis gamma-secretase and presenilin activity to spine ER dynamics.