School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong.
Mol Psychiatry. 2021 Jun;26(6):2533-2552. doi: 10.1038/s41380-020-01005-w. Epub 2021 Jan 20.
Synaptic deficit-induced excitation and inhibition (E/I) imbalance have been implicated in the pathogenesis of schizophrenia. Using in vivo two-photon microscopy, we examined the dynamic plasticity of dendritic spines of pyramidal neurons (PNs) and "en passant" axonal bouton of parvalbumin-expressing interneurons (PVINs) in the frontal association (FrA) cortex in two adolescent mouse models with schizophrenia-like behaviors. Simultaneous imaging of PN dendritic spines and PV axonal boutons showed that repeated exposure to N-methyl-D-aspartate receptor (NMDAR) antagonist MK801 during adolescence disrupted the normal developmental balance of excitatory and inhibitory synaptic structures. This MK801-induced structural E/I imbalance significantly correlated with animal recognition memory deficits and could be ameliorated by environmental enrichment (EE). In addition, selective chemogenetic activation of PVINs in the FrA mimicked the effects of EE on both synaptic plasticity and animal behavior, while selective inhibition of PVIN abolished EE's beneficial effects. Electrophysiological recordings showed that chronic MK801 treatment significantly suppressed the frequency of mEPSC/mIPSC ratio of layer (L) 2/3 PNs and significantly reduced the resting membrane potential of PVINs, the latter was rescued by selective activation of PVINs. Such manipulations of PVINs also showed similar effects in PV-Cre; ErbB4 animal model with schizophrenia-like behaviors. EE or selective activation of PVINs in the FrA restored behavioral deficits and structural E/I imbalance in adolescent PV-Cre; ErbB4 mice, while selective inhibition of PVINs abolished EE's beneficial effects. Our findings suggest that the PVIN activity in the FrA plays a crucial role in regulating excitatory and inhibitory synaptic structural dynamics and animal behaviors, which may provide a potential therapeutic target for schizophrenia treatment.
突触缺失引起的兴奋和抑制（E/I）失衡与精神分裂症的发病机制有关。使用活体双光子显微镜，我们检查了两个具有类似精神分裂症行为的青春期小鼠模型中额前联合（FrA）皮层锥体神经元（PNs）和表达钙调蛋白结合蛋白 I 型（PVINs）的“沿途”轴突末梢的树突棘的动态可塑性。PN 树突棘和 PV 轴突末梢的同时成像表明，青春期反复暴露于 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂 MK801 会破坏兴奋性和抑制性突触结构的正常发育平衡。这种 MK801 诱导的结构 E/I 失衡与动物识别记忆缺陷显著相关，并且可以通过环境丰富（EE）得到改善。此外，FrA 中 PVINs 的选择性化学遗传激活模拟了 EE 对突触可塑性和动物行为的影响，而 PVINs 的选择性抑制消除了 EE 的有益效果。电生理记录显示，慢性 MK801 处理显著抑制了 L2/3 PNs 的 mEPSC/mIPSC 频率比，并显著降低了 PVINs 的静息膜电位，后者可通过选择性激活 PVINs 得到挽救。这种对 PVINs 的操作在具有类似精神分裂症行为的 PV-Cre; ErbB4 动物模型中也显示出类似的效果。EE 或 FrA 中 PVINs 的选择性激活恢复了青春期 PV-Cre; ErbB4 小鼠的行为缺陷和结构 E/I 失衡，而 PVINs 的选择性抑制消除了 EE 的有益效果。我们的发现表明，FrA 中的 PVIN 活性在调节兴奋性和抑制性突触结构动力学和动物行为方面起着至关重要的作用，这可能为精神分裂症的治疗提供一个潜在的治疗靶点。
