Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder

Abstract

Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including “axon guidance” and “regulation of actin cytoskeleton.” In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.

Comparative Gene Expression Analysis of Two Mouse Models of Autism: Transcriptome Profiling of the BTBR and En2−/− Hippocampus

“…We detected a total of 1016 BTBR DEGs, whereas the number of BTBR DEGs detected by Daimon et al (2015) was significantly lower (301). Only 69 BTBR DEGs were common to the two datasets.…”

Serotonin neuron abnormalities in the BTBR mouse model of autism

“…Several other hippocampal abnormalities have been reported in the BTBR mouse including: age‐dependent changes in 5‐HT 1A receptors [Gould et al, ], severely reduced hippocampal commissure [Wahlsten, Metten, & Crabbe, ], reduced hippocampal neurogenesis, reduced hippocampal BDNF expression [Stephenson et al, ] several altered features of synaptic plasticity [MacPherson, McGaffigan, Wahlsten, & Nguyen, ; Seese, Maske, Lynch, & Gall, ; Scattoni, Martire, Cartocci, Ferrante, & Ricceri, ], and marked transcriptional changes [Daimon et al, ]. In fact, the reduction of BDNF could be a causal factor for the loss of serotonin innervation: BDNF is a known trophic factor for serotonin axons and reduction in BDNF expression is associated with loss of hippocampal serotonin innervation [Lyons et al, ; Mamounas et al, ].…”

The BTBR mouse model of idiopathic autism – Current view on mechanisms

“…natural language processing-based informatics analysis allowed for extraction of functional groups of altered genes. These included: axon guidance , neurogenesis and regulation of actin cytoskeleton (Daimon et al 2015). …”

“…As indicated by transcriptomic and proteomic studies, axon guidance, neurogenesis (Daimon et al 2015) as well as myelination (Wei et al 2016a) and oligodendrocyte generation (Jasien et al 2014, Wei et al 2016a) are differently regulated in BTBR brains as compared with B6 mice. The combination of the acallosal phenotype with decreased neurogenesis (Stephenson et al 2011) displayed by BTBR mice provides a unique opportunity to study the role of both of these factors in the development of normosocial behaviors.…”