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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Effects of environmental enrichment and sexual dimorphism on the expression of cerebellar receptors in C57BL/6 and BTBR + Itpr3tf/J mice
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The authors would like to thank the HKU Faculty Core Facility for their technical support on imaging experiments and the HKU Laboratory Animal Unit for their support on animal husbandry. The authors would like to thank Leonard W. Cheung for his support on mouse genotyping. The authors would like to thank Christ C. Wong for his support on MATLAB-based programs. This work was supported by the Hong Kong Research Grants Council (RGC/ECS 27103715 and RGC/GRF 17128816 to CSWL, RGC/ECS 21103818 and RGC/GRF 11104320 to CGL), the National Natural Science Foundation of China (NSFC/General Program 31571031 to CSWL), Shenzhen General Basic Research Program (JCYJ20190808182203591 to CGL), and the Health and Medical Research Fund (HMRF 03143096 to CSWL).
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Huang, Y., Jiang, H., Zheng, Q. et al. Environmental enrichment or selective activation of parvalbumin-expressing interneurons ameliorates synaptic and behavioral deficits in animal models with schizophrenia-like behaviors during adolescence. Mol Psychiatry 26, 2533–2552 (2021). https://doi.org/10.1038/s41380-020-01005-w
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