National Centre for Biological Science, Tata Institute of Fundamental Research, Bangalore, 560065, India.
Sastra University, Thirumalaisamudram, Thanjavur, Tamil Nadu 613401, India.
J Neurosci. 2021 Apr 28;41(17):3777-3798. doi: 10.1523/JNEUROSCI.2401-20.2021. Epub 2021 Mar 18.
The stromal interaction molecule 1 (STIM1) is an ER-Ca sensor and an essential component of ER-Ca store operated Ca entry. Loss of STIM1 affects metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic transmission, neuronal Ca homeostasis, and intrinsic plasticity in Purkinje neurons (PNs). Long-term changes of intracellular Ca signaling in PNs led to neurodegenerative conditions, as evident in individuals with mutations of the ER-Ca 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 KO mice ( ) of both sexes across ages. Our study identified a requirement for STIM1-mediated Ca 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 mice. Together, our data identify STIM1 as an important regulator of Ca 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. In Purkinje neurons (PNs), the stromal interaction molecule 1 (STIM1) is required for mGluR1-dependent synaptic transmission, refilling of ER Ca 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.
基质相互作用分子 1（STIM1）是内质网钙传感器，也是内质网钙储存操纵的钙进入的必需组成部分。STIM1 的缺失会影响代谢型谷氨酸受体 1（mGluR1）介导的突触传递、神经元钙稳态和浦肯野神经元（PNs）的内在可塑性。PNs 中细胞内钙信号的长期变化导致神经退行性疾病，这在内质网钙通道、肌醇 1,4,5-三磷酸受体的突变个体中显而易见。在这里，我们询问由于 STIM1 的缺失，内在神经元特性的变化是否会对 PNs 产生年龄依赖性影响。因此，我们分析了跨年龄段雄性和雌性 PN 特异性 KO 小鼠（）的 mRNA 表达谱和小脑形态。我们的研究确定了 STIM1 介导的钙信号在维持突触功能和神经突发育等关键生物学网络中基因表达所必需的。基因表达变化与树突形态的改变以及更多的 climbing 纤维对 PN 树突的神经支配相关，在衰老的小鼠中。总之，我们的数据表明，STIM1 是钙稳态和神经元兴奋性的重要调节剂，反过来对于维持 PN 随年龄增长的最佳转录谱是必需的。我们的发现对于理解失调的钙信号如何影响多种神经退行性疾病中的细胞机制具有重要意义。在浦肯野神经元（PNs）中，基质相互作用分子 1（STIM1）是 mGluR1 依赖的突触传递、内质网 Ca 储存再填充、频率调节和小脑记忆巩固所必需的。在这里，我们提供了 STIM1 在维持 PNs 的基因表达谱和最佳突触连接中的新作用的证据。与神经突发育和突触组织网络相关的基因表达在持续缺失 STIM1 的 PNs 中发生改变。与这些发现一致，PNs 的树突形态和 climbing 纤维对 PNs 的神经支配也随着年龄的增长而发生显著变化。这些发现确定了失调的细胞内钙信号在神经退行性疾病中的新作用，并提供了新的治疗见解。
