Spatiotemporal expression of autism-related and FMRP target genes in the FMR1 knock out mouse model

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and repetitive behaviours. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines ASD as an umbrella term for the following four separate disorders: autistic disorder, Asperger disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified. Currently, there is no empirical biological method to diagnose ASD patients. While advances have been made in understanding ASD, development of new treatments is limited. Fragile X Syndrome (FXS) has become pertinent to elucidating a biological understanding of ASD. FXS is the most common heritable single gene cause of ASD, and is caused by 200 or more CGG trinucleotide repeats in the Fragile X Mental Retardation 1 (FMR1) gene, which silences the function of the gene through epigenetic mechanisms. This thesis aims to identify the neurobiological underpinnings of Fragile X Syndrome as this serves as a gateway into understanding the  complexity and heterogeneity of ASD. Using in situ hybridization, three genes are examined for their spatiotermporal expression across the hippocampus and somatosensory cortex (S1) brain regions. All samples were collected from wild type (WT) and fragile X mice during postnatal development. Target genes were selected to meet the following two criteria: 1) identified gene variants in ASD individuals and 2) known FMR1 protein targets. Significant differences were observed in PTEN mRNA between WT and fragile X mice at postnatal day 21 in both the S1 and dentate gyrus brain regions. No significant differences were found between WT and fragile X mice for CHD8 and SYNGAP1 mRNA. This approach will further the ongoing analysis of the underlying biological basis of ASD, which is necessary for optimizing therapeutics in the future.

Written by Daiana Pogacean, Katerina Liaconis, Jonathan Lai, Jane A. Foster

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