Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Cell Rep. 2019 Feb 19;26(8):2037-2051.e6. doi: 10.1016/j.celrep.2019.01.092.
Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increases expression of postsynaptic GABA receptor β2/3-subunits and neuroligin 3, enhancing synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered E/I balance and circuit dysfunction in CYFIP1-associated neurological disorders.
兴奋性/抑制性（E/I）平衡的改变与神经精神和神经发育障碍有关，但潜在的遗传病因仍知之甚少。CYFIP1 的拷贝数变异与自闭症、精神分裂症和智力障碍有关，但它在调节突触抑制或 E/I 平衡中的作用仍不清楚。我们表明，CYFIP1 和其同源物 CYFIP2 在抑制性突触后位点富集。虽然 CYFIP1 或 CYFIP2 的上调增加了兴奋性突触的数量和微小兴奋性突触后电流（mEPSC）的频率，但在抑制性突触上却产生相反的效果，减少了它们的大小和微小抑制性突触后电流（mIPSCs）的幅度。与 CYFIP1 的上调相反，其在体内的缺失，即在新皮层主要神经元中的条件性敲除，增加了突触后 GABA 受体 β2/3-亚基和神经连接蛋白 3 的表达，增强了突触抑制。因此，CYFIP1 的剂量可以双向影响抑制性突触的结构和功能，可能导致与 CYFIP1 相关的神经发育障碍中的 E/I 平衡和电路功能障碍。
