Parvalbumin Interneuron Activation-Dependent Adult Hippocampal Neurogenesis Is Required for Treadmill Running to Reverse Schizophrenia-Like Phenotypes.

Yandong Yi,Yuanlong Song,Yisheng Lu

doi:10.3389/fcell.2020.00024

Abstract

Physical exercise can alleviate some of the schizophrenia symptoms in patients, the mechanisms, however, are still unclear. To investigate whether the GABAergic interneuron involved in the therapeutic effect of treadmill running on schizophrenia, the parvalbumin (PV)-positive GABAergic interneurons in the dentate gyrus (DG) was specifically activated or abolished and the effects were evaluated. In the MK801-induced schizophrenia-like animal model, we found:(1) Treadmill running rescued the schizophrenia-related behavioral phenotypes, promoted the adult hippocampal neurogenesis, and increased the dendrite number and complexity of newborn neurons. (2) Treadmill running increased the number of PV-positive interneurons in the DG; genetic ablation of these interneurons reduced adult neurogenesis and abolished the effect of treadmill running on the schizophrenia-related behaviors. Consistently, chemogenetic activation of these interneurons improved neurogenesis and alleviated the schizophrenia-related behaviors. These results suggest a pivotal role of PV-positive interneuron-mediated adult neurogenesis in exercise. (3) However, schizophrenia-related behavioral phenotypes and adult neurogenesis in the DG could still be reversed by exercise after specifically knocking out the schizophrenia-related gene ErbB4 in PV interneurons, as a means to reduce their GABA release. These results suggest that activation of PV interneurons in the DG is sufficient for treadmill running to reverse schizophrenia-like phenotypes.

Highlights

Schizophrenia is a serious chronic mental disorder that affects approximately 1% of the world’s population since their adolescence or early adulthood, placing a high economic burden for individuals and society (Wu et al, 2006; Chang et al, 2017)
We found in MK801-induced schizophrenialike animal models, adult neurogenesis and schizophreniarelated behavior phenotypes could be rescued by treadmill running
Our study confirms that PV neurons in the dentate gyrus (DG) are critical for the action of treadmill running in reversing schizophrenialike phenotypes by promoting adult neurogenesis

Summary

Introduction

Schizophrenia is a serious chronic mental disorder that affects approximately 1% of the world’s population since their adolescence or early adulthood, placing a high economic burden for individuals and society (Wu et al, 2006; Chang et al, 2017). Schizophrenia symptoms can be classified into three categories: positive, negative, and cognitive. Parvalbumin Activation Reduces Schizophrenia Risk hallucinations and delusions are treatable with antipsychotic drugs, whereas negative symptoms like affection blunt and cognitive symptoms are almost not amenable with drugs (Goldberg et al, 2007). Clinical investigations have indicated that physical exercise is effective in alleviating negative and cognitive symptoms in patients with schizophrenia (Rosenbaum et al, 2014; Firth et al, 2015; Dauwan et al, 2016), but the mechanism is largely unknown. Studies from postmortem (Pedersen and Cohen, 1990; Falkai et al, 2016), fibroblasts-derived induced pluripotent stem cell (iPSC) from patients with schizophrenia (Yu et al, 2014), and genetic or pharmacological animal models of schizophrenia (Pereira et al, 2007; Christian et al, 2014; Allen et al, 2016) have revealed that dysregulation of adult neurogenesis in the SGZ of the DG is associated with schizophrenia; adult hippocampal neurogenesis impairment can induce schizophrenia-related behavioral phenotypes, especially cognitive symptoms (Reif et al, 2006; Mao et al, 2009), and promotion of adult neurogenesis in the SGZ can rescue behavioral deficits in schizophrenia animal models (Ouchi et al, 2013; Wu et al, 2017)

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Results

Conclusion