Abstract
Schizophrenia is a debilitating disorder affecting just under 1% of the population. While the symptoms of this disorder do not appear until late adolescence, pathological alterations likely occur earlier, during development in utero. While there is an increasing literature examining transcriptome alterations in patients, it is not possible to examine the changes in gene expression that occur during development in humans that will develop schizophrenia. Here we utilize three distinct rodent developmental disruption models of schizophrenia to examine potential overlapping alterations in the transcriptome, with a specific focus on markers of interneuron development. Specifically, we administered either methylazoxymethanol acetate (MAM), Polyinosinic:polycytidylic acid (Poly I:C), or chronic protein malnutrition, on GD 17 and examined mRNA expression in the developing hippocampus of the offspring 18 hours later. Here, we report alterations in gene expression that may contribute to the pathophysiology of schizophrenia, including significant alterations in interneuron development and ribosome function.
Highlights
599 differentially expressed genes were identified out of a total of 5211 genes with measured expression (S1 Table). These were obtained using a threshold of 0.05 for statistical significance (p-value). These data were analyzed in the context of pathways obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (Release 81.0+/01-20, Jan 17)[36,37], gene ontologies from the Gene Ontology Consortium database (2016-Sep26) [38], predicted miRNAs from the miRBase (Release 21) and MICROCOSM (Microsm version: v5) databases[39,40,41,42,43,44], and diseases from the KEGG database (Release 81.0+/01-20, Jan 17) [36,37]
503 Gene Ontology (GO) terms, 15 miRNAs, and 3 diseases were found to be significantly enriched based on uncorrected p-values (S1 Table)
Viral infection during pregnancy has been associated with an increased risk of schizophrenia in humans[5,49,50,51] and administration of the viral mimetic, polyriboinosinic-polyribocytidilic acid (Poly I:C), on gestational day 17 has been shown to produce anatomical, physiological, and behavioral deficits that resemble schizophrenia
Summary
Schizophrenia is a debilitating psychiatric disorder that affects just under 1% of the population [1]. As early as the 1980’s, it was proposed that schizophrenia was a neurodevelopmental disorder[2,3]. Evidence for this theory comes from the observation that prenatal complications such as maternal infection[4,5,6,7,8] and famine[9,10,11,12,13] significantly increase the risk of developing psychosis; and postmortem studies reveal neuroanatomical alterations indicative of abnormal neuronal development (i.e. heterotopias[14,15]). Many of the genes implicated in schizophrenia have been associated with neurodevelopmental processes[16,17] and the etiology of schizophrenia overlaps with the etiology of other neurodevelopmental disorders, like autism[18].
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