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

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. 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. 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. 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.