RBFOX3/NeuN is required for hippocampal circuit balance and function

RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders. Two samples (one is from wild-type and the other is from Rbfox3 homozygous knockout mice)RBFOX3突变（RBFOX3）与癫痫及认知功能损害密切相关，但目前对这类疾病的潜在病理生理机制仍知之甚少。本研究在Rbfox3敲除小鼠模型中复现了人类相关病症表型：Rbfox3敲除小鼠表现出癫痫易感性升高，且焦虑相关行为减少。本研究聚焦海马表型，发现Rbfox3敲除小鼠的突触可塑性相关基因Egr4与Arc表达上调，且其穿通通路存在突触传递与突触可塑性缺陷。突变型齿状颗粒细胞的兴奋性突触事件频率升高，但振幅维持正常，该变化与神经递质释放概率提升及树突棘密度增加相关。综上，本研究结果证实Rbfox3敲除小鼠存在解剖学与功能学异常，可为RBFOX3相关人类脑部疾病提供潜在的机制阐释。本研究共包含两份样本：一份来自野生型小鼠，另一份来自Rbfox3纯合敲除小鼠。