Environmental enrichment or selective activation of parvalbumin-expressing interneurons ameliorates synaptic and behavioral deficits in animal models with schizophrenia-like behaviors during adolescence

帕尔瓦布明 神经科学 兴奋性突触后电位 突触可塑性 抑制性突触后电位 树突棘 NMDA受体 心理学 电生理学 精神分裂症(面向对象编程) 化学 生物 受体 内科学 医学 海马结构 精神科
作者
Yuhua Huang,Hehai Jiang,Qi‐Yu Zheng,Albert Hiu Ka Fok,Xiaoyang Li,C. Geoffrey Lau,Cora Sau Wan Lai
出处
期刊:Molecular Psychiatry [Springer Nature]
卷期号:26 (6): 2533-2552 被引量:40
标识
DOI:10.1038/s41380-020-01005-w
摘要

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; ErbB4fl/fl 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; ErbB4fl/fl 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.
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