The role of ADAMTS2 in schizophrenia: Validation in a novel transgenic mouse model

Abstract Despite decades of research, therapeutic progress in psychiatric disorders has been limited, partly due to the lack of mechanistically valid genetic models to interrogate disease biology. Among these disorders, schizophrenia (SCZ) is characterized by heterogeneous clinical symptoms and limited therapeutic efficacy, and its molecular mechanisms remain incompletely understood. Among candidate genes, ADAMTS2, a metalloprotease involved in extracellular matrix (ECM) remodeling, has emerged as a potential biomarker and modulator of SCZ pathophysiology. ADAMTS2 is implicated in the proteolytic processing of Reelin, a glycoprotein crucial for neurodevelopment and synaptic function whose dysregulation has been associated with SCZ. Here, we generated a transgenic mouse model (ADAMTS2-Cre) with forebrain-specific overexpression of human ADAMTS2 in glutamatergic neurons to elucidate its role in Reelin signaling and SCZ-relevant molecular and behavioral phenotypes. ADAMTS2 overexpression induced a significant reduction in full-length Reelin levels and an increased accumulation of the Reelin N-R2 fragment in the prefrontal cortex, accompanied by male-specific social deficits, female-specific stress-related/passive behaviors, and impaired recognition memory across sexes. No significant changes were observed in Dab1 expression or hippocampal Reelin processing, suggesting region-specific effects and potential compensatory mechanisms involving other ADAMTS family members. These findings support a role for ADAMTS2-mediated Reelin processing in the molecular and behavioral features of SCZ and identify ADAMTS2 as a potential therapeutic target for modulating ECM-related dysfunction in psychiatric disorders. The ADAMTS2-Cre mouse represents a novel and valuable tool for further exploration of ECM proteolytic balance in SCZ pathophysiology.