What is it about?
Disruption of brain development early in life may underlie the neurobiology behind schizophrenia. We have reported more immature synaptic spines in the frontal cortex (FC) of adult Roman High-Avoidance (RHA-I) rats, a behavioural model displaying schizophrenia-like traits. Here, we performed a whole transcriptome analysis in the FC of 4 months old male RHA-I (n=8) and its counterpart, the Roman Low-Avoidance (RLA-I) (n=8). We identified 203 significant genes with overrepresentation of genes involved in synaptic function. Next, we performed a gene set enrichment analysis (GSEA) for genes co-expressed during neurodevelopment. Gene networks were obtained by weighted gene co-expression network analysis (WGCNA) of a transcriptomic dataset containing human FC during lifespan (n=269). Out of thirty-one functional gene networks, six were significantly enriched in the RHA-I. These were differentially regulated during infancy and enriched in biological ontologies related to myelination, synaptic function, and immune response. We validated differential gene expression in a new cohort of adolescent (<=2 months old) and young-adult (>=3 months old) RHA-I and RLA-I rats. The results confirmed overexpression of Gsn, Nt5cd1, Ppp1r1b, and Slc9a3r1 in young-adult RHA-I, while Cables1, a regulator of Cdk5 phosphorylation in actin regulation and involved in synaptic plasticity and maturation, was significantly downregulated in adolescent RHA-I. This age-related expression change was also observed for presynaptic components Snap25 and Snap29. Our results show a different maturational expression profile of synaptic components in the RHA-I strain, supporting a shift in FC maturation underlying schizophrenia-like behavioural traits and adding construct validity to this strain as a neurodevelopmental model.
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Why is it important?
This study uses Roman High-Avoidance (RHA-I) rats as a model of schizophrenia to investigate how changes in synaptic gene expression during frontal cortex maturation contribute to schizophrenia-like behaviors. Key findings include transcriptomic changes in synaptic gene networks, delayed synaptic maturation similar to that observed in human schizophrenia, and age-dependent gene expression changes. RHA-I rats exhibit behavioral deficits that reflect negative and cognitive symptoms of schizophrenia, such as prepulse inhibition and nesting behavior alterations. Additionally, epigenomic alterations influenced by antipsychotic treatment and aging were observed. This model validates RHA-I rats for studying the neurodevelopmental origins of schizophrenia, highlighting altered synaptic maturation as a core pathological mechanism, and provides a valuable tool for researching this complex disorder.
Perspectives
This study on RHA-I rats as a schizophrenia model opens up several exciting perspectives for future research and clinical applications. By providing insights into the neurodevelopmental origins of schizophrenia, particularly the role of altered synaptic maturation, it paves the way for more targeted therapeutic interventions. The age-dependent gene expression changes observed could lead to the development of stage-specific treatments, potentially improving outcomes for patients at different phases of the disorder. The model's ability to replicate both behavioral and molecular aspects of schizophrenia makes it a valuable tool for testing new drugs and interventions before human trials. Furthermore, the epigenomic findings suggest potential for reversibility of some synaptic changes, which could inform novel treatment strategies. Lastly, this research underscores the importance of considering developmental trajectories in psychiatric disorders, potentially influencing how we approach diagnosis and treatment of schizophrenia and related conditions in the future.
Carles Tapias Espinosa
Read the Original
This page is a summary of: A maturational shift in the frontal cortex synaptic transcriptional landscape underlies schizophrenia-relevant behavioural traits: A congenital rat model, European Neuropsychopharmacology, September 2023, Elsevier,
DOI: 10.1016/j.euroneuro.2023.05.001.
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