Mutation of gabra1 is associated with hypermotility and abnormal expression of proteins critical for ion homeostasis and synaptic vesicle transport.

Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy phenotypes. GABRA1 encodes for the α1 subunit of the gamma-aminobutyric acid type A receptor (GABA A R), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have previously been developed to understand the mechanism by which mutations in GABRA1 cause disease, but these models have produced complex and incongruent data. Thus, additional model systems are required to validate and substantiate previously published results. We investigated the behavioral patterns associated with a non-sense mutation of the zebrafish gabra1 ( sa43718 allele) gene. The sa43718 allele has a 90% decrease in total gabra1 mRNA expression, which is associated with light induced seizure-like behavior. Mutation of gabra1 was accompanied by increased mRNA expression of gabra4 , which encodes for the alpha-4 subunit of the GABA A R. Despite increased expression at the RNA level, Gabra4 protein was not increased according to proteomics analysis. Thus, implying that RNA expression patterns of alpha sub-units may not accurately reflect the mechanism underlying seizure. Interestingly, proteomics analysis identified significant enrichment of genes that regulate proton transport, ion homeostasis, vesicle transport, and mitochondrial protein complexes. Collectively, our analysis validates that mutation of gabra1 results in seizure like phenotypes and provides a blueprint of putative proteins which may mediate these phenotypes in vivo .