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

Molecular Psychiatry volume 26, pages 2533–2552 (2021)Cite this article

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Abstract

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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Fig. 1: EE prevents MK801-induced aberrant structural excitation and inhibition balance and deficit in a novel object recognition task.
Fig. 2: Selective excitation of PVINs in the FrA mimics, while inhibition of PVINs abolishes the beneficial effects of EE on MK801-induced structural excitation and inhibition imbalance and deficit in a novel object recognition task.
Fig. 3: Selective excitation of PVINs ameliorates MK801-induced dendritic spine plasticity of L2/3 PNs and synaptic deficits in L2/3 PNs and PVINs in ex vivo electrophysiology recordings.
Fig. 4: Selective excitation of PVINs mimics, while inhibition of PVINs abolishes the therapeutic effects of EE on synaptic plasticity and animal behaviors under post-MK801 treatment.
Fig. 5: Selective excitation of PVINs mimics, while inhibition of PVINs erases the therapeutic effects of EE on synaptic plasticity and animal behaviors in conditional knockout of ErBb4 mice.

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Acknowledgements

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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  1. School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

    Yuhua Huang, Qiyu Zheng, Albert Hiu Ka Fok, Xiaoyang Li & Cora Sau Wan Lai

  2. Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong

    Hehai Jiang & C. Geoffrey Lau

  3. Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong

    Hehai Jiang & C. Geoffrey Lau

  4. State Key Laboratory of Cognitive and Brain Research, The University of Hong Kong, Pokfulam, Hong Kong

    Cora Sau Wan Lai

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Contributions

YH and CSWL designed the experiments. YH performed behavioral tests, DREADDs viral infections, in vivo imaging experiments, and analyzed the data. HJ and CGL carried out the in vitro electrophysiological experiments and analyzed the data. QZ performed immunostaining experiments and analyzed PV somatic boutons imaging data. AHKF performed plasmid constructs cloning and in utero electroporation experiments. XL performed stereotaxic retrograde viral injections. YH and CSWL wrote and edited the manuscript with comments from all of the other authors.

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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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  • DOI: https://doi.org/10.1038/s41380-020-01005-w

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