A NOVEL ROLE FOR THE ER-CALCIUM SENSOR STIM2 IN REGULATING DENDRITIC SPINE MORPHOGENESIS AND AMPA RECEPTOR TRAFFICKING

Abstract

This thesis explores the interaction of the endoplasmic reticulum (ER) with excitatory synapses in the mammalian nervous system and focuses, in particular, on the role of the ER-resident STIM2 protein on synapse formation, structure and function. STIM2 but not STIM1, was shown to regulate the formation of dendritic spines and shape spontaneous synaptic transmission in excitatory neurons. Furthermore, STIM2 can translocate into puncta in dendrites and dendritic spines in response to cyclic adenosine monophosphate (cAMP) elevation, and mediates protein kinase A (PKA)-dependent phosphorylation of the GluA1 subunit of the AMPA receptor. This phosphorylation event is mediated by local assembly of a STIM2-AKAP79/150-PKA complex that promotes AMPA receptor surface delivery through opposing effects on GluA1 exocytosis and endocytosis, thus regulating activity-dependent surface delivery of the AMPA receptor. Collectively, this study suggests a novel mechanism of synaptic plasticity in which the ER communicates with the synapse through dynamic assembly of a PKA signaling complex at ER-PM contact sites.