Hydroxychloroquine alleviates maternal separation-induced schizophrenia-like behaviors by preventing autophagic degradation of TRPV1

Abstract

Previous studies have shown that schizophrenia is closely related to transient receptor potential vanilloid1 (TRPV1). It is reported that downregulation of TRPV1 occurs in animals undergoing maternal separation (MS) which can induce behaviors and pathology reminiscent of schizophrenia. In vitro, cortisol was found to degrade TRPV1 via autophagy induction. Hydroxychloroquine (HCQ), an autophagy inhibitor, is recognized as an effective treatment to lower the risk of central nervous system degenerative diseases. This study aimed to explore whether HCQ can alleviate schizophrenia-like behaviors by modulating TRPV1 in a MS induced schizophrenia model. HCQ was administered at a dose of 2 mg/kg to rats just before MS on postnatal day 9 (PND9). Behavioral tests and measurements of biological markers were undertaken on PND10 and in adulthood. Furthermore, autophagy and TRPV1 levels were detected in the HT22 cells model. The results showed that autophagy levels increased in the hippocampus and prefrontal cortex of PND10 in MS rats, accompanied by decreased TRPV1. MS rats in adulthood showed impaired autophagy function and neuronal apoptosis in the hippocampus and prefrontal cortex, accompanied by schizophrenia-like behaviors. Early treatment with HCQ reverses these changes in MS rats and alleviates behavioral abnormalities. Our findings in the HT22 cells model confirmed the link between TRPV1 and autophagy. In summary, our findings suggest that HCQ prevents TRPV1 degradation via autophagy, alleviating MS-induced neurobiological and behavioral alterations.