Clozapine induces perineuronal net remodeling in a developmental mouse model exhibiting schizophrenia-relevant phenotypes.

Schizophrenia (SCZ) is a multifaceted neurodevelopmental disorder characterized by widespread dysregulation of extracellular matrix (ECM) components, particularly perineuronal nets (PNNs), which are crucial for synaptic stability and cognitive function. Alterations in PNNs, especially in the prefrontal cortex (PFC), have been linked to cognitive deficits in SCZ. While antipsychotic (AP) treatments have been suggested to influence PNNs and ECM integrity, their specific effects remain unclear. In this study, we used a neurodevelopmental mouse model exhibiting SCZ-relevant phenotypes, induced by perinatal NMDA receptor hypofunction through ketamine administration, to investigate the impact of PNN alterations and their modulation by clozapine (CLZ), an atypical AP, in adulthood. We found that ketamine exposure led to increased PNN thickness and reduced structural complexity (i.e., more compact and less porous PNNs), elevated VGLUT1-mediated excitatory inputs, and dysregulated medial PFC network activity, characterized by hyperactivation of surviving PV interneurons and a disrupted excitation/inhibition balance. Treatment with CLZ mitigated these changes by partially restoring PNN microarchitecture and enhancing the structural integrity and porosity of PNNs in the medial PFC. Additionally, CLZ-mediated effects on PNNs were associated with improvements in cognitive flexibility and social memory, functions tightly linked to PFC-dependent processing. These findings suggest that CLZ's actions on PNN structure may contribute to its therapeutic effects in conditions involving prefrontal cortical dysfunction, as observed in SCZ, although these correlations require further investigation to confirm their causal relevance. Overall, our results underscore the need for further investigation into the impact of AP medications on PNN plasticity and ECM integrity.