Chd2 is necessary for neural circuit development and long-term memory. Chd2 is necessary for neural circuit development and long-term memory

Considerable evidence suggests loss of function mutations in the chromatin remodeler, CHD2, contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show Chd2+/- mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2+/- mice, including alterations in neurogenesis, synaptic transmission and disease-related genes. Deficits in interneuron density and memory caused by Chd2+/- were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory. Overall design: We examined RNA expression levels between Chd2+/- and WT from E13.5 MGE, E13.5 cortex, and P45 Hippocampus.

大量研究证据表明，染色质重塑因子（chromatin remodeler）CHD2的功能丧失突变可引发广谱人类神经发育疾病。然而目前尚不清楚CHD2突变如何导致脑功能受损。本研究构建了携带Chd2杂合突变的小鼠模型，发现其存在神经元增殖缺陷，且神经元兴奋性发生改变，具体表现为兴奋性与抑制性突触功能出现背离性变化。进一步的体内实验显示，Chd2+/-小鼠表现出异常皮层节律发生以及严重的长期记忆缺陷，这与人类患者中观察到的表型一致。我们在Chd2+/-小鼠中鉴定到广泛的、年龄依赖性的转录组变化，涵盖神经发生、突触传递以及疾病相关基因的表达改变。Chd2+/-导致的中间神经元密度缺陷与记忆缺陷，可通过将Chd2突变限制在特定亚群的抑制性神经元中重现，并可通过中间神经元移植得以矫正。本研究结果首次揭示了Chd2单倍体剂量不足（haploinsufficiency）如何导致异常皮层网络功能与记忆受损。实验设计：我们检测了来自胚胎第13.5天（embryonic day 13.5, E13.5）内侧神经节隆起（medial ganglionic eminence, MGE）、胚胎第13.5天大脑皮层以及出生后第45天（postnatal day 45, P45）海马体的Chd2+/-小鼠与野生型（wild type, WT）小鼠的RNA表达水平。