GABA

GABA (Gamma-Aminobutyric acid) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a principal role in reducing neuronal excitability throughout the nervous system. In humans, GABA also functions as a key signalling molecule in the brain^[1].

GABA is synthesized in the brain from its precursor, glutamate, via the action of the enzyme glutamic acid decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. GAD exists in two isoforms, GAD65 and GAD67, named after their respective molecular weights^[2].

Once synthesised, GABA is packed into synaptic vesicles by vesicular inhibitory amino acid transporter (VIAAT or VGAT). Upon synaptic vesicle fusion, GABA is released into the synaptic cleft and can interact with two classes of receptors: the ionotropic GABA_A receptors and the metabotropic GABA_B receptors^[3].

When GABA binds to GABA_A receptors, it typically causes an influx of chloride ions into the neuron, making the inside of the neuron more negatively charged and thus less likely to fire an action potential. GABA_B receptors, on the other hand, are coupled to G-proteins and work via second messenger systems, which can lead to both short-term changes in cell excitability and long-term changes in gene expression^[4].

After its release and binding to receptors, GABA is rapidly removed from the synaptic cleft by GABA transporters (GATs) found in neurons and glial cells. Inside the neuron, GABA can be broken down by the enzyme GABA transaminase (GABA-T) into succinic semialdehyde, which is then converted into succinate by the enzyme succinic semialdehyde dehydrogenase. Succinate is a component of the tricarboxylic acid cycle (also known as the Krebs cycle or citric acid cycle), a key biochemical pathway in cellular respiration^[6].

GABAergic neurons can be found distributed throughout the CNS. This includes areas such as the cerebral cortex, hippocampus, and the basal ganglia among others. GABAergic interneurons are particularly important in the cerebral cortex and hippocampus, where they regulate the activity and timing of excitatory neurons and thereby influence the flow of information through neural circuits. GABAergic neurons are also found in the hypothalamus, where they contribute to the regulation of hormone release, and in the brainstem, where they play roles in regulation of heart rate, blood pressure, and temperature, among other things^[8].

In the spinal cord, GABAergic neurons contribute to motor control and the processing of sensory information.