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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.

SUBMITTER: Daimon CM

PROVIDER: S-EPMC4656818 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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

Daimon Caitlin M CM Jasien Joan M JM Wood William H WH Zhang Yongqing Y Becker Kevin G KG Silverman Jill L JL Crawley Jacqueline N JN Martin Bronwen B Maudsley Stuart S

Frontiers in physiology 20151124

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 c ...[more]

PMID: 26635614

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Project description:BackgroundAutism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes.MethodsPregnant female mice received VPA (600 mg/kg, ip) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs).ResultsEarly adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal.ConclusionsThis study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.

Dataset Information

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

Publications

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

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