Woolfrey Kevin M, Srivastava Deepak P, Photowala Huzefa, Yamashita Megumi, Barbolina Maria V, Cahill Michael E, Xie Zhong, Jones Kelly A, Quilliam Lawrence A, Prakriya Murali, Penzes Peter
Department of Physiology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Nat Neurosci. 2009 Oct;12(10):1275-84. doi: 10.1038/nn.2386. Epub 2009 Sep 6.
Dynamic remodeling of spiny synapses is crucial for cortical circuit development, refinement and plasticity, whereas abnormal morphogenesis is associated with neuropsychiatric disorders. We found that activation of Epac2, a PKA-independent cAMP target and Rap guanine-nucleotide exchange factor (GEF), in cultured rat cortical neurons induced spine shrinkage, increased spine motility, removed synaptic GluR2/3-containing AMPA receptors and depressed excitatory transmission, whereas its inhibition promoted spine enlargement and stabilization. Epac2 was required for dopamine D1-like receptor-dependent spine shrinkage and GluR2 removal from spines. Epac2 interaction with neuroligin promoted its membrane recruitment and enhanced its GEF activity. Rare missense mutations in the EPAC2 (also known as RAPGEF4) gene, previously found in individuals with autism, affected basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution and spine morphology. Thus, we identify a previously unknown mechanism that promotes dynamic remodeling and depression of spiny synapses, disruption of which may contribute to some aspects of disease.
棘状突触的动态重塑对于皮质回路的发育、精细化和可塑性至关重要，而异常的形态发生与神经精神疾病相关。我们发现，在培养的大鼠皮质神经元中，激活Epac2（一种不依赖PKA的cAMP靶点和Rap鸟嘌呤核苷酸交换因子（GEF））会诱导棘突收缩，增加棘突运动性，去除含突触GluR2/3的AMPA受体并抑制兴奋性传递，而抑制它则会促进棘突增大和稳定。Epac2是多巴胺D1样受体依赖性棘突收缩和从棘突中去除GluR2所必需的。Epac2与神经连接蛋白的相互作用促进了其膜募集并增强了其GEF活性。先前在自闭症个体中发现的EPAC2（也称为RAPGEF4）基因中的罕见错义突变影响了基础和神经连接蛋白刺激的GEF活性、树突状Rap信号传导、突触蛋白分布和棘突形态。因此，我们确定了一种以前未知的促进棘状突触动态重塑和抑制的机制，其破坏可能导致疾病的某些方面。
