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Disruption of brain development early in life may underlie the neurobiology behind schizophre-nia. 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 net-works, 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 im-mune 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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Matthias Wolf, Henry Markram, Felix Schürmann, Eilif Benjamin Muller, Srikanth Ramaswamy, Michael Reimann, Daniel Keller, Werner Alfons Hilda Van Geit, James Gonzalo King, Pramod Shivaji Kumbhar, Alexis Arnaudon, Jean-Denis Georges Emile Courcol, Rajnish Ranjan, Armando Romani, András Ecker, Michael Emiel Gevaert, Vishal Sood, Sirio Bolaños Puchet, James Bryden Isbister, Judit Planas Carbonell, Daniela Egas Santander, Maria Reva, Genrich Ivaska, Natali Barros Zulaica, Mustafa Anil Tuncel, Christoph Pokorny, Elvis Boci, Jorge Blanco Alonso, Aleksandra Zuzanna Teska, Darshan Mandge, Polina Litvak, Gianluca Ficarelli, Weina Ji, Giuseppe Chindemi, Christian Andreas Rössert, Omar Awile, Joni Henrikki Herttuainen, Samuel Lieven D. Lapere, Thomas Brice Delemontex, Tanguy Pierre Louis Damart, Alexander Dietz