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

Schizophrenia (SCZ) is a complicated psychiatric disorder characterized by positive symptoms (e.g., hallucinations and delusions), negative symptoms (e.g., social withdrawal and anhedonia) and pervasive cognitive deficits []. Among the affected brain regions, the medial prefrontal cortex (mPFC) — a hub for working memory [], cognitive flexibility [], and social behavior [] — has been prominently recognized as a central locus of the illness []. Convergent evidence from genetics, neuroimaging, and postmortem studies reveals multi-level disturbances in the mPFC, ranging from aberrant synaptic gene expression [] and altered dendritic architecture [] to disrupted neural oscillations [], collectively indicating impairment of cortical microcircuit function []. For decades, the prevailing neurobiological framework of SCZ has focused primarily on neuronal dysfunction, particularly glutamatergic and GABAergic signaling deficits. However, therapeutic interventions derived from these models provided only partial symptomatic relief [], suggesting that neuronal dysfunction alone may not fully account for disease pathophysiology. Astrocytes, the principal glial cell type in the central nervous system, are now recognized as active regulators of synaptic transmission rather than passive support cells []. By sensing and releasing gliotransmitters such as glutamate, ATP, and D-serine, astrocytes precisely modulate synaptic efficacy and maintain extracellular homeostasis []. Disruption of these astrocyte-neuron interactions may therefore perturb local microcircuit coordination and impair cortical information processing. Accumulating evidence indicates that astrocytic abnormalities are consistent features of SCZ []. Genetic studies have shown significant enrichment of astrocyte-related gene sets in SCZ brains [, ], while postmortem analyses further reveal altered astrocytic density and morphology in the PFC of patients []. In line with these observations, transplantation of glial progenitor cells derived from SCZ patients into neonatal mice delays astrocyte maturation and recapitulates SCZ-like behaviors []. Collectively, these findings position astrocyte dysfunction as a biologically meaningful component of SCZ pathophysiology. However, the specific mechanisms by which impaired astrocyte-neuron communication drives circuit-level deficits remain a critical gap in our understanding.