Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that is naturally present in the central nervous system. It plays a crucial role in the regulation of neuronal excitability and balance between excitatory and inhibitory activity of the brain. GABA binds to two types of receptors, ionotropic receptors (GABA-A and GABA-C) and metabotropic receptors (GABA-B) [1]. Its binding to ionotropic receptors triggers the opening of chloride ion channels present in the neural membrane. The following influx of chloride ions hyperpolarizes the neuron, reducing its excitability by decreasing its chances of getting activated by an action potential. GABA-B receptor inhibition or activation upon GABA binding results in the modulation of ion channels, neurotransmitter release, and membrane potentials, allowing a fine-tuning of the neuron activity in the brain [2].
If you want to take a deeper dive into GABA, check out our in-depth guide here. In this article, we'll focus on the symptoms and causes of GABA deficiency. However, if you're aware of these signs and would instead like to find ways to help increase GABA levels naturally, or if you're curious about whether or not GABA supplements work, read here.
GABA synthesis and metabolism
GABA is synthesized from glutamate, which is a principal excitatory neurotransmitter produced from glutamine through glutaminase activity, by the glutamate decarboxylase (GAD) enzyme through the GABA pathway. Both GAD variants, GAD65 and GAD67, require pyridoxal-5′-phosphate, the active form of vitamin B6, as an allosteric cofactor to decarboxylate glutamate [3].
Another enzyme, known as GABA transaminase (GABA-T), clears released GABA from the synapses by converting it back into glutamate [4].
Both GAD and GABA-T are highly expressed in the brain. Additionally, GAD is expressed in the pancreas, while GABA-T is found in the liver and to a lower extent in the pancreas and kidneys [4].
GABA roles in humans
In the brain, GABA participates in the balance-controlling cognitive functions and emotional responses along with glutamate, and this regulation is influenced by neuromodulators such as dopamine and acetylcholine [2]. GABA is also known for its calming effects and ability to induce sleepiness when activating GABA-A receptors [5]. GABA also inhibits unwanted motor signals and is involved in the maintenance of respiratory rate from the medulla. In the spinal cord, GABA neurons help with the excitatory proprioceptive signals and the integration of sensory information to allow smooth movements [6-8]. Finally, in the pancreas, GABA inhibits alpha cells, stimulates beta-cell growth, and converts alpha cells into beta cells [6]. Although GABA is also found in other organs, its significance and function at these other sites are still unclear and require further studies.
If you're curious about how GABA works with sleep hormones such as melatonin, serotonin, and others, read here.
Clinical significance of GABA
Numerous drugs can modulate the GABAergic system. For example, benzodiazepines are agonists (activators) of GABA-A receptors. They are used to treat epilepsy, rapid eye movement sleep disorders, alcohol withdrawal, essential tremor, and muscle spasticity [9].
Symptoms of low levels of GABA
Disruptions in the balance between excitatory and inhibitory transmission are implicated in several psychiatric disorders, including anxiety disorders, depression, and schizophrenia [2]. Deficit in GABA or low GABA levels is associated with insomnia, irritability, attention deficit hyperactivity disorder, and epilepsy. It may also cause dystonia and spasticity, and the lack of GABA is partially responsible for the motor symptoms in Huntington's and Parkinson’s disease [4,9,10].
Causes of GABA deficiency
GABA deficiency can result from various factors impacting its synthesis, metabolism, or receptor function. A deficit in vitamin B6 can disrupt GABA levels as its activated form, pyridoxine, is a crucial co-factor for GAD to synthesize GABA [7]. Similarly, inadequate intake of other nutrients required for GABA synthesis or receptor function, such as glutamate (GABA precursor), magnesium [11], or zinc [12], can contribute to GABAergic system deficiency. Stress and depression also alter GABA transmission. Several studies (in humans and rodents) have reported alterations in GAD expression, lower GABA levels, and fewer GABA-A and GABA-B receptors in specific regions of the brain [10,13,14].
Chronic alcohol consumption can also disrupt GABA neurotransmission. Alcohol initially increases GABA activity, leading to sedative effects, but chronic use can downregulate GABA receptors, resulting in GABA deficiency when alcohol is withdrawn [15-18].
Finally, infections can also disrupt GABA levels. Toxoplasma gondii, a protozoan parasite, uses GABA as a carbon source for its metabolism and interferes with the signaling of GABA in the brain. Experiments in mice showed that these parasite-induced changes in GAD67 distribution resulted in the development of spontaneous seizures. These data suggest that seizures and other neurological complications seen in human toxoplasmosis patients are due, at least in part, to changes in GABAergic signaling [19]. Post-acute COVID-19 syndrome, also known as Long-COVID, is also linked to reduced GABA levels, which correlate with depression and poor sleep quality in affected patients [20].
Conclusion
GABA plays a critical role in the brain and has potential implications for mental and physical health. Factors causing GABA deficiency can individually or collectively contribute to alterations of the GABAergic system leading to neurological symptoms.
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References
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