Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, China.
Nat Commun. 2021 Jan 12;12(1):278. doi: 10.1038/s41467-020-20552-y.
Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Na1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Na currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.
皮层去抑制是精神分裂症、自闭症和智力障碍等几种神经精神疾病的共同特征。然而，其潜在的机制尚不完全清楚。为了模拟精神分裂症患者 GABA 能中间神经元中 NRG1 表达增加的情况，我们在 GABA 能中间神经元中过表达 Nrg1 生成了 gtoNrg1 小鼠。gtoNrg1 小鼠在细胞、突触、神经网络和行为水平上表现出皮层去抑制。我们揭示了 NRG1 的细胞内结构域与 Na1.1 的细胞质环 1 相互作用，Na1.1 是 GABA 能中间神经元兴奋性的关键钠离子通道，可抑制 Na 电流。有趣的是，激活 GABA 能中间神经元或在成年期恢复 NRG1 的表达可挽救 gtoNrg1 小鼠的过度活跃和社交新奇性损伤。这些结果确定了与精神分裂症相关的皮层去抑制的潜在机制，并提出了恢复 NRG1 信号和 GABA 能功能可能对某些神经精神疾病有益的可能性。
