TY - JOUR

T1 - A maturational shift in the frontal cortex synaptic transcriptional landscape underlies schizophrenia-relevant behavioural traits

T2 - A congenital rat model

AU - Sønderstrup, Marie

AU - Batiuk, Mykhailo Y.

AU - Mantas, Panagiotis

AU - Tapias-Espinosa, Carles

AU - Oliveras, Ignasi

AU - Cañete, Toni

AU - Sampedro-Viana, Daniel

AU - Brudek, Tomasz

AU - Rydbirk, Rasmus

AU - Khodosevich, Konstantin

AU - Fernandez-Teruel, Alberto

AU - Elfving, Betina

AU - Aznar, Susana

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Behavioural animal model

KW - Bioinformatics

KW - Neurodevelopmental disorder

KW - Prefrontal cortex

KW - Schizophrenia

KW - Transcriptomics

U2 - 10.1016/j.euroneuro.2023.05.001

DO - 10.1016/j.euroneuro.2023.05.001

M3 - Journal article

C2 - 37263043

AN - SCOPUS:85160509704

VL - 74

SP - 32

EP - 46

JO - European Neuropsychopharmacology

JF - European Neuropsychopharmacology

SN - 0924-977X

ER -