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Authors & Affiliations
Blanca Sánchez-Moreno, Ángela Calzado-González, Ana Isabel Fraga-Sánchez, Inés García-Ortiz, Miriam Martínez-Jiménez, Claudio Toma, David Vega-Avelaira, Javier Gilabert-Juan
Abstract
Aims: This study aims to elucidate the transcriptomic changes underlying thalamic alterations in an animal model of schizophrenia. Methods: We used a 'dual hit' rat model of schizophrenia, which combines an injection of non-competitive NMDA receptor antagonist MK-801 at P7 and 8 weeks of postweaning social isolation. The model was developed in both male and female rats. At 3 months, behavioral tests and RNA sequencing (RNAseq) of the thalamus were performed. Differential expressed genes (DEGs) and enriched categories were validated in silico via MAGMA using GWAS summary statistics of the Psychiatric Genomics Consortium of schizophrenia (67,390 cases and 94,015 controls). Results: Regarding behavioral measurements, male model rats showed a decreased preference for sucrose and increased hypermobility and time spend in the center in the open field test when compared to controls. The same trend was found in female rats, but with no statistical significance. In the RNAseq analysis, combined male and female enriched categories after validation pointed to synaptic membranes and glutamatergic synapse, attention deficit hyperactivity disorder (ADHD), seizures, and long-term potentiation. Conclusions: These results indicate that our 'dual hit' rat model of schizophrenia does recapitulate some of the symptoms seen in schizophrenia patients. RNAseq results highlight the importance of the synaptic function in schizophrenia, suggesting possible shared genetic pathways between schizophrenia, ADHD and epilepsy. This study provides a valuable model of sex-specific molecular alterations for further investigations in the pathophysiology of schizophrenia.