Schizophrenia-associated glycoprotein Adamtsl3 regulates perineuronal net formation, maintenance, and adult cortical...

Perineuronal nets (PNNs) regulate the maturation of parvalbumin-positive (PV+) interneurons during postnatal critical periods and continue to support their function thereafter. Their disruption is implicated in neuropsychiatric disorders such as schizophrenia, yet key endogenous PNN regulators remain unknown. Here, we identify the schizophrenia-associated glycoprotein Adamtsl3 as a PV+ cell-autonomous regulator of PNN integrity. Using mouse genetics, morphological and biochemical analyses, we demonstrate that Adamtsl3 deletion, both in early postnatal and adult stages, results in PNN deficits. Mechanistically, Adamtsl3 modulates matrix metalloprotease-9 (MMP9) activity, and Adamtsl3 deletion results in elevated MMP9 levels, PNN reduction, decreased Otx2 uptake, and heightened oxidative stress in PV+ cells. MMP9 hyperactivity and PNN reduction can be rescued by pharmacological inhibition of MMP9. Deletion of Adamtsl3 in PV+ interneurons revealed its cell-autonomous function in modulating PNN integrity. Notably, conditional Adamtsl3 deletion in adult PV+ cells reactivated juvenile-like ocular dominance plasticity. These results position Adamtsl3 as a persistent, PV+ specific PNN regulator with direct implications for the pathophysiology of schizophrenia.