FROM LOCAL NETWORK DISRUPTION TO NEUROIMMUNE REMODELING: RETROSPLENIAL CORTEX ALTERATIONS IN MOUSE MODELS OF COGNITIVE IMPAIRMENT RELEVANT TO SCHIZOPHRENIA

Schizophrenia (SCZ) is a severe, chronic illness characterized by positive, negative, and cognitive symptoms. Cognitive impairment in SCZ is debilitating and is associated with substantial disruptions in the default mode network (DMN). As a heavily interconnected posterior midline region and a major node of the DMN, the retrosplenial cortex (RSC) is involved in a range of cognitive functions, including memory and spatial navigation. Although SCZ-related alterations in DMN regions accompanied by microglial overactivation have been described, how cellular and network dysfunction in RSC and its association with neuroimmune activation disrupts DMN functional connectivity remains poorly defined.

Using ketamine as a pharmacological model of SCZ-relevant cognitive deficits, male and female C57BL/6 mice received either acute (single-dose) or chronic (14-injections) ketamine (30 mg/kg) or vehicle. Acute and chronic ketamine impaired spatial and non-spatial cognitive abilities, respectively. To relate these impairments to alterations in neuronal and microglial physiology, we used in vivo two-photon imaging and confocal microscopy. Consistent with the behavioral results, imaging in Thy1-GCaMP6s transgenic mice revealed distortions in neuronal spike-related activity, accompanied by changes consistent with inhibitory network alterations in the RSC. The chronic ketamine robustly activated microglia and reduced perineuronal nets (PNNs) surrounding parvalbumin-positive interneurons in the RSC. Depleting microglia during the chronic regimen abolished ketamine-induced PNN loss, identifying microglia as a necessary mediator of this remodeling. Microglial depletion also attenuated ketamine-associated behavioral impairments, alongside relative preservation of PNN integrity, consistent with the histological pattern. Ongoing analyses are examining how microglia-driven PNN remodeling could reshape RSC microcircuit dynamics in SCZ.