Astrocytic connexin 43 hemichannel dysregulation drives prefrontal circuit dysfunction and schizophrenia-like behaviors

Schizophrenia (SCZ) is hypothesized to arise from neural circuit dysfunction, but the role of non-neuronal cells remains poorly defined. While astrocytic connexin 43 (Cx43) facilitates both gap junction (GJ) coupling and hemichannel (HC)-mediated gliotransmitter release, its specific role in SCZ remains unclear. Here, we report elevated Cx43 expression in the prefrontal cortex of individuals with SCZ and investigate its functional relevance in an MK801-induced mouse model. In this model, medial prefrontal cortex (mPFC) Cx43 upregulation was associated with enhanced HC activity without affecting GJ coupling. Pharmacological blockade of Cx43 HC with TAT-Gap19 rescued SCZ-like behavioral and synaptic alterations, whereas astrocyte-specific Cx43 overexpression (Cx43 OE) in the mPFC of naive mice recapitulated behavioral abnormalities. Mechanistically, increased HC activity was linked to excessive astrocytic glutamate release, which was directly visualized using ex vivo two-photon imaging with an astrocyte-specific glutamate sensor and normalized by TAT-Gap19. Together, our results integrate human expression data with experimental evidence to implicate astrocytic Cx43 HC dysregulation in prefrontal circuit dysfunction relevant to SCZ and suggest that glial HC signaling warrants further investigation in SCZ pathophysiology.