EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of Epac2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs.

中文翻译：

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EPAC2的丢失会改变树突棘的形态和抑制突触的密度。

EPAC2是鸟嘌呤核苷酸交换因子，可调节小GTPase Rap和Ras的GTPase活性，并在突触处高度富集。EPAC2的激活已显示可诱导树突状脊柱收缩并增加脊柱运动性，这是突触可塑性所必需的。这些形态学效应因与自闭症谱系障碍相关的Epac2罕见突变而失调。另外，EPAC2通过去除含有突触的GluA2 / 3的AMPA受体来破坏突触的稳定性。先前的研究表明，Epac2基因敲除小鼠（Epac2-/-）表现出异常的社交互动，以及额叶皮层的严重混乱和体内异常的脊柱运动。在这项研究中，我们试图进一步了解敲除Epac2对神经元和突触结构以及皮层神经元组织的细胞后果。使用从Epac2 + / +或Epac2-/-小鼠产生的原代皮层神经元，我们确认EPAC2是依赖cAMP的脊柱收缩所必需的。来自Epac2-/-小鼠的神经元还显示出含有GluA2 / 3的AMPA受体以及粘附蛋白N-钙粘着蛋白的突触表达增加。有趣的是，对兴奋性和抑制性突触蛋白的分析显示，EPAC2的缺失会导致水泡GABA转运蛋白（VGAT）的表达发生改变，但不会引起水泡谷氨酸转运蛋白1（VGluT1）的表达变化，表明神经元上的兴奋性和抑制性突触比率发生了变化。最后，对位于前扣带回皮层中的皮质神经元的检查进一步揭示了体内树突状树突形成过程中的细微缺陷。这些数据提供了证据，即EPAC2的缺失增强了兴奋性突触的稳定性并增加了抑制性输入的数量。