Purkinje Neurons with Loss of STIM1 Exhibit Age-Dependent Changes in Gene Expression and Synaptic Components.

The stromal interaction molecule 1 (STIM1) is an ER-Ca2+ sensor and an essential component of ER-Ca2+ store operated Ca2+ entry. Loss of STIM1 affects metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic transmission, neuronal Ca2+ homeostasis, and intrinsic plasticity in Purkinje neurons (PNs). Long-term changes of intracellular Ca2+ signaling in PNs led to neurodegenerative conditions, as evident in individuals with mutations of the ER-Ca2+ channel, the inositol 1,4,5-triphosphate receptor. Here, we asked whether changes in such intrinsic neuronal properties, because of loss of STIM1, have an age-dependent impact on PNs. Consequently, we analyzed mRNA expression profiles and cerebellar morphology in PN-specific STIM1 KO mice (STIM1PKO ) of both sexes across ages. Our study identified a requirement for STIM1-mediated Ca2+ signaling in maintaining the expression of genes belonging to key biological networks of synaptic function and neurite development among others. Gene expression changes correlated with altered patterns of dendritic morphology and greater innervation of PN dendrites by climbing fibers, in aging STIM1PKO mice. Together, our data identify STIM1 as an important regulator of Ca2+ homeostasis and neuronal excitability in turn required for maintaining the optimal transcriptional profile of PNs with age. Our findings are significant in the context of understanding how dysregulated calcium signals impact cellular mechanisms in multiple neurodegenerative disorders.SIGNIFICANCE STATEMENT In Purkinje neurons (PNs), the stromal interaction molecule 1 (STIM1) is required for mGluR1-dependent synaptic transmission, refilling of ER Ca2+ stores, regulation of spike frequency, and cerebellar memory consolidation. Here, we provide evidence for a novel role of STIM1 in maintaining the gene expression profile and optimal synaptic connectivity of PNs. Expression of genes related to neurite development and synaptic organization networks is altered in PNs with persistent loss of STIM1. In agreement with these findings the dendritic morphology of PNs and climbing fiber innervations on PNs also undergo significant changes with age. These findings identify a new role for dysregulated intracellular calcium signaling in neurodegenerative disorders and provide novel therapeutic insights.