id_783. THE SCHIZOPHRENIA-ASSOCIATED 3Q29 DELETION MODIFIES BEHAVIORAL AND MOLECULAR RESPONSE TO ACUTE RISPERIDONE TREATMENT IN A MOUSE MODEL
Magdalena Ziemiańska1, Klaudia Misiołek1, Julia Netczuk1, Martyna Boguska1, Łukasz Szumiec1, Sławomir Gołda1, Mateusz Zięba2, Marcin Piechota2, Małgorzata Borczyk2, Marzena Maćkowiak3, Michał Korostyński2, Jan Ridriguez Parkitna1
1 Departament of Molecular Neuropharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
2 Laboratory of Pharmacogenomics, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
3 Department of Pharmacology and Brain Biostructure, Maj Institute of Pharmacology Polish
INTRODUCTION: Rare high-risk schizophrenia variants may contribute to variability in antipsychotic response, yet their mechanistic effects remain unclear. The 3q29 deletion, conferring >40-fold increased risk, is conserved in mice, providing a translational model to investigate disease mechanisms and treatment efficacy.
AIM(S): We investigated behavioral and transcriptomic responses to acute risperidone treatment in a mouse model of the human 3q29 deletion.
METHOD(S): Adult mutant and wild-type littermates were tested in two sessions, measuring acoustic startle and prepulse inhibition (PPI). Baseline responses were assessed in drug-naïve animals, followed by administration of risperidone (0.5 or 1 mg/kg) or saline in the second session. Brains were collected two hours after 1 mg/kg treatment for spatial transcriptomic profiling.
RESULTS: Mice carrying the 3q29 deletion exhibited elevated acoustic startle amplitudes while maintaining intact PPI, indicating increased baseline stimulus-evoked responding without impairment of sensorimotor gating. Acute risperidone treatment suppressed startle amplitude in both genotypes but produced a smaller reduction in PPI in 3q29 mice than in control mice, revealing blunted antipsychotic effects in mutants. At the molecular level, spatial transcriptomic analysis confirmed reduced expression of genes within the 3q29 deleted region. Following risperidone treatment, 64 genes showed genotype-dependent expression changes. Gene ontology analysis revealed enrichment for biological processes involving learning, synaptic plasticity, and sensorimotor function. Notably, 13 of these 64 genes are associated with schizophrenia risk.
CONCLUSIONS: Together, these findings demonstrate that genetic risk shapes behavioral and transcriptional responses to antipsychotic treatment. They validate the 3q29 mouse model for studying schizophrenia etiology and indicate that risperidone modulates genes implicated in disease risk.
FINANCIAL SUPPORT: This work was supported by National Science Centre, Poland NCN OPUS UMO-2020/39/B/NZ7/01494