Effects of environmental enrichment on cortical synaptic plasticity in mouse models of schizophrenia : involvement of parvalbumin interneurons

Abstract

N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin-expressing interneuron (PV interneuron) deficit are both implicated in the pathogenesis of schizophrenia. Pharmacological NMDAR antagonism has been widely used as an animal model for studying the pathogenesis of schizophrenia. However, the effects of NMDAR antagonism on the structural plasticity of excitatory and inhibitory synapses during development remain unexplored.

Using in vivo two-photon microscopy, the dynamic plasticity of the dendritic spine of pyramidal neurons and en passant axonal bouton of PV interneurons (PV axonal bouton) in mouse frontal association cortex (FrA) was examined in an NMDAR antagonism model. It was found that repeated exposure to the NMDAR antagonist dizocilpine maleate (MK801) during adolescence induced schizophrenic-related behaviors and significant reduction of dendritic spine formation of layer 5 pyramidal neurons in a dose-dependent manner. Simultaneous longitudinal imaging of dendritic spine of layer 5 pyramidal neurons and en passant axonal bouton of layer 2/3 PV interneurons showed that MK801 disrupted the normal developmental balance of excitatory and inhibitory (E/I) synaptic structures by enhancing the elimination of PV axonal boutons and reducing the formation of dendritic spines and PV axonal boutons. This MK801-induced structural E/I imbalance was ameliorated by environmental enrichment (EE), and the structural E/I value significantly correlated with animal working memory in novel object recognition. Besides, selective chemogenetic activation of PV interneurons in the FrA mimicked the effects of EE on both the dendritic spine and PV axonal bouton dynamics and animal behaviors, while selective inhibition of PV interneurons abolished the beneficial effects of EE.

In addition, the dynamic plasticity of the dendritic spine of layer 2/3 pyramidal neurons was also studied in the NMDAR antagonism model. It was found that repeated exposure to MK801 during adolescence caused not only a reduction in the rate of spine formation but also an enhancement in the rate of spine elimination. Furthermore, EE exerted a delayed beneficial effect on dendritic spine plasticity of layer 2/3 pyramidal neurons when compared to layer 5, while selective activation of PV interneurons in the FrA showed no such delay in repeated exposure of MK801. On the other hand, selective inhibition of PV interneurons abolished the beneficial effects of EE on layer 2/3 dendritic spine plasticity.

Next, I asked whether the involvement of PV interneurons in the beneficial action of EE on synapses and behavior can also apply to the genetic model of schizophrenia. Here a PV-Cre; ErbB4fl/fl conditional knockout (cKO) mouse, where ErbB4 was selectively ablated in PV interneurons, was used. It was found that the cKO mice displayed schizophrenia-like behaviors and both dendritic spine and PV axonal bouton deficits during adolescence, while these behavioral and synaptic deficits were rescued by activating frontal PV interneurons.

Collectively, these findings suggest that the PV interneuron activity in the FrA is crucial for excitatory and inhibitory synaptic structural dynamics and animal behavior in NMDAR hypofunction and PV interneuron deficits schizophrenia animal models, which demonstrate the crucial roles of PV interneuron activity and provide a potential therapeutic target for the treatment of schizophrenia.