PDF(Pubmed)
Abstract：
Reactive astrocytes play a pivotal role in the pathogenesis of neurological diseases; however, their functional phenotype and the downstream molecules by which they modify disease pathogenesis remain unclear. Here, we genetically increase P2Y1 receptor (P2Y1R) expression, which is upregulated in reactive astrocytes in several neurological diseases, in astrocytes of male mice to explore its function and the downstream molecule. This astrocyte-specific P2Y1R overexpression causes neuronal hyperexcitability by increasing both astrocytic and neuronal Ca2+ signals. We identify insulin-like growth factor-binding protein 2 (IGFBP2) as a downstream molecule of P2Y1R in astrocytes; IGFBP2 acts as an excitatory signal to cause neuronal excitation. In neurological disease models of epilepsy and stroke, reactive astrocytes upregulate P2Y1R and increase IGFBP2. The present findings identify a mechanism underlying astrocyte-driven neuronal hyperexcitability, which is likely to be shared by several neurological disorders, providing insights that might be relevant for intervention in diverse neurological disorders.
摘要：
反应性星形胶质细胞在神经系统疾病的发病机制中起着举足轻重的作用;它们的功能表型和改变疾病发病机制的下游分子仍不清楚.这里,我们基因增加P2Y1受体（P2Y1R）的表达，在几种神经系统疾病的反应性星形胶质细胞中上调，在雄性小鼠星形胶质细胞中探讨其功能及其下游分子。这种星形胶质细胞特异性P2Y1R过表达通过增加星形细胞和神经元Ca2信号引起神经元过度兴奋。我们将胰岛素样生长因子结合蛋白2（IGFBP2）鉴定为星形胶质细胞中P2Y1R的下游分子；IGFBP2作为兴奋性信号引起神经元兴奋。在癫痫和中风的神经系统疾病模型中，反应性星形胶质细胞上调P2Y1R并增加IGFBP2。本研究发现了星形胶质细胞驱动的神经元兴奋过度的潜在机制，这可能是几种神经系统疾病共有的，提供可能与多种神经系统疾病干预相关的见解。
