TRPV1 Suppresses Microglial Inflammatory Activation to Ameliorate Schizophrenia-Associated Behaviors in Maternal Separation Rats

Abstract Background and Hypothesis Schizophrenia is linked to hippocampal dysfunction and microglial inflammatory activation. Our prior clinical findings revealed significantly reduced transient receptor potential vanilloid 1 (TRPV1) expression in both first-episode and recurrent schizophrenia patients, with levels inversely correlating with symptom severity, implicating TRPV1 dysfunction in disease progression. Preclinical maternal separation (MS) models recapitulate schizophrenia-like behavioral and synaptic deficits, paralleled by hippocampal microglial TRPV1 downregulation. We hypothesize that early-life stress-induced TRPV1 deficiency in microglia disrupts the calmodulin-dependent protein kinase II (CaMKII)/nuclear factor-erythroid 2-related factor 2 (NRF2)/Sirtuin 3 (SIRT3) signaling axis, thereby amplifying microglial inflammatory responses and synaptic dysfunction underlying cognitive and behavioral impairments. Study Design Using a 24-h acute MS model in postnatal day 9 rats, we assessed hippocampal microglial TRPV1 expression, synaptic plasticity, and schizophrenia-like behaviors. Pharmacological (capsaicin, CAP) and genetic (adeno-associated virus (AAV)-mediated overexpression/knockdown (KD)) TRPV1 manipulations were applied. Co-cultures of TRPV1-knockout (KO) microglia and neurons were used to dissect cell-specific effects. Study Results MS reduced microglial TRPV1, increased pro-inflammatory cytokines, and induced hyperlocomotion, cognitive deficits, and impaired sensory gating. CAP or microglial TRPV1 overexpression restored synaptic plasticity and reversed behavioral deficits. Conversely, TRPV1 KD worsened neuronal dysfunction. TRPV1-KO microglia, but not neurons, promoted inflammation and neuronal damage via CaMKII/NRF2/SIRT3 downregulation. Conclusions These findings provided novel insights into the role of microglial TRPV1 in schizophrenia pathogenesis, establishing it as an upstream regulator of the CaMKII/NRF2/SIRT3 signaling axis—a pathway not previously linked to TRPV1 in neuroinflammation. Our work identifies microglia-specific TRPV1 modulation as a new therapeutic strategy for schizophrenia, highlighting its therapeutic potential for cognitive and negative symptoms in schizophrenia.