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

Schizophrenia is a highly complex polygenic neurodevelopmental disorder that typically emerges during adolescence or early adulthood. Although substantial progress has been made in identifying genetic risk factors, the biological mechanisms linking gene dysregulation to disease onset remain poorly understood. In previous transcriptomic analyses of peripheral blood from patients with schizophrenia, we identified six genes significantly overexpressed at disease onset (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B). Notably, the expression of these genes returned to baseline levels following three months of antipsychotic treatment in clinically responsive patients. Among these candidates, ADAMTS2 showed the highest degree of overexpression, suggesting a potential role as both a biomarker and mechanistic contributor to disease pathology. ADAMTS2 encodes a secreted metalloprotease involved in extracellular matrix remodelling and has been shown to mediate the N-terminal cleavage and functional inactivation of Reelin, a glycoprotein strongly implicated in schizophrenia. This positions ADAMTS2 as a plausible mediator between peripheral molecular alterations and central neurodevelopmental dysfunction in schizophrenia.

The present study aimed to determine whether increased ADAMTS2 expression contributes directly to schizophrenia-related phenotypes and to investigate its effects on Reelin processing in vivo. To address this, we generated a forebrain-specific knock-in mouse model overexpressing ADAMTS2. Genotypic frequency, mortality, body weight and developmental progression were assessed across sex and age. Behavioural phenotyping included tests of locomotor activity, social interaction, anxiety-like behaviour and stress-related responses. Molecular analyses of the prefrontal cortex were conducted to quantify Reelin expression and the accumulation of its cleavage products. Statistical analyses were performed using two-way or Student t-test analysis of variance according to the number of experimental factors, followed by Tukey’s post hoc test for multiple comparisons.

ADAMTS2 overexpression did not alter Mendelian inheritance, survival, body weight or developmental progression at any time point analysed, indicating that the transgene does not impair general viability. Behavioural analyses revealed pronounced sexual dimorphism. Male transgenic mice exhibited increased locomotor activity and deficits in social interaction, consistent with phenotypes associated with positive and social symptom domains of schizophrenia. Female transgenic mice, by contrast, showed enhanced stress-related responses and behavioural alterations suggestive of increased vulnerability to affective dysregulation. These effects were observed across multiple paradigms and were dependent on both genotype and sex. At the molecular level, transgenic animals displayed reduced levels of full-length Reelin in the prefrontal cortex together with significant accumulation of the N-R2 cleavage fragment, confirming enhanced ADAMTS2-mediated processing of this schizophrenia-associated protein.

These findings demonstrate that forebrain overexpression of ADAMTS2 is sufficient to induce behavioural and molecular alterations relevant to schizophrenia, with distinct sex-specific phenotypic profiles. The disruption of Reelin signalling provides mechanistic evidence linking ADAMTS2 dysregulation to neurobiological pathways implicated in the disorder. Collectively, these results support further investigation of ADAMTS2 as a potential contributor to schizophrenia pathophysiology and treatment responsiveness.

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