Altered GABAergic Signaling in Brain Disease at Various Stages of Life

In the healthy brain, gamma-aminobutyric acid (GABA) is regulated by neurons and glia. This begs the question: what happens in the malfunctioning brain? There are many reasons why diseases occur, including genetic mutations, systemic problems, and environmental influences. There are also many ways in which GABA can become dysregulated, such as through alterations in its synthesis or release, and changes in systems that respond to it. Notably, dysregulation of GABA can have a large impact on the brain. To date, few reviews have examined brain diseases in which dysregulation of GABA is implicated as an underlying factor. Accordingly, the time is ripe for investigating alterations in GABAergic signaling that may play a role in changes in neuronal activity observed in the major brain disorders that occur during various stages of life. This review is meant to provide a better understanding of the role of GABA in brain health and contributor to social problems from a scientific perspective.

Decreased Glial GABA and Tonic Inhibition in Cerebellum of Mouse Model for Attention-Deficit/Hyperactivity Disorder (ADHD)

About 5~12% of school-aged children suffer from the Attention-Deficit/Hyperactivity Disorder (ADHD). However, the core mechanism of ADHD remains unclear. G protein-coupled receptor kinase-interacting protein-1 (GIT1) has recently been reported to be associated with ADHD in human and the genetic deletion of GIT1 result in ADHD-like behaviors in mice. Mice lacking GIT1 shows a shift in neuronal excitation/inhibition (E/I) balance. However, the pricise mechanism for E/I imbalance and the role of neuron-glia interaction in GIT1 knockout (KO) mice have not been studied. Especially, a possible contribution of glial GABA and tonic inhibition mediated by astrocytic GABA release in the mouse model for ADHD remains unexplored. Therefore, we investigated the changes in the amount of GABA and degree of tonic inhibition in GIT1 KO mice. We observed a decreased glial GABA intensity in GIT1 KO mice compared to wild type (WT) mice and an attenuation of tonic current from cerebellar granule cells in GIT1 KO mice. Our study identifies the previously unknown mechanism of reduced astrocytic GABA and tonic inhibition in GIT1 lacking mice as a potential cause of hyperactivity disorder.