Gama-aminobutyric acid (GABA) is the key inhibitory transmitter in the central nervous system of adults. It has a crucial role in maintaining the proper balance of excitation to inhibition and is therefore key in the regulation of brain development and neural circuitry. GABA is formed by the decarboxylation of glutamate by the enzyme glutamic acid decarboxylase (GAD). In humans, GAD has two isoforms, GAD65 and GAD67, which arise from Gad2 and Gad1, respectively. Issues with GAD1 have been associated with multiple neurological disorders, such as epilepsy, schizophrenia, and autism spectrum disorder (ASD). While the exact mechanisms behind the cause of these neurological disorders are not well known, it is believed that mutations in a GAD gene would lead to decreased GABA signaling, which in turn would alter the excitatory to inhibitory balance. Disruptions in this balance are thought to cause dysregulation of synaptic pruning resulting in decreased circuitry refinement. However, studying the effects of decreased GABA levels throughout development has been challenging due to a lack of viable GAD mutants in most model organisms, particularly mice. In zebrafish, a genome duplication event gave rise to paralogs of GAD, gad1a and gad1b. Our lab was able to generate CRISPR mutants of gad1a null larvae and gad1b null larvae that are viable. Characterization of these animals has identified the gad1b mutants as candidates for studying the effects chronic decreased GABA signaling has on brain development, particularly on neural circuitry refinement and sensory processing by using light sheet calcium imaging, light sheet volumetric imaging, and an optomotor response behavioral assay. Through these studies, evidence of altered neural circuitry, a decreased excitatory-to-inhibitory cell ratio in a subset of cells essential for visual processing, and impairments in visual processing have been elucidated.
