Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of the brain and plays an essential role in balancing the neuronal excitatory and inhibitory activity. In the presynaptic neuron, glutamic acid decarboxylase converts glutamate into GABA, which is stored in vesicles. Upon neuronal excitation, GABA is released into the synapse by exocytosis and binds to GABA receptors on the postsynaptic membrane [1].
GABA interacts with two receptor types: ionotropic receptors (GABA-A, GABA-C) and metabotropic receptors (GABA-B) [2]. Its binding to ionotropic receptors triggers the opening of chloride ion channels in the neural membrane and hyperpolarizes the neuron, decreasing its chances of getting activated. GABA-B receptor activation modulates ion channels, neurotransmitter release, and membrane potentials, allowing a fine-tuning of neurons’ activity [3]. After binding to its receptor, GABA transporters on glial cells uptake the remaining GABA from the synaptic cleft. Then, GABA transaminase converts GABA back to glutamate, or succinate semialdehyde dehydrogenase fully degrades it [1]. GABA synthesis, release, receptor interactions, and inactivation form the GABAergic system, which, along with glutamate, dopamine, and acetylcholine, contributes to the balance that regulates cognitive functions and emotional responses [3]. Any abnormalities in GABA metabolism, including variants in genes encoding enzymes responsible for GABA synthesis and degradation, transporters, and receptors, may lead to diseases.
This article provides an overview of genetic variants identified in various components of the GABAergic system and their association with different diseases. (Please note that this is not an exhaustive list; it is just the most common!)
Genetic variants in the glutamate decarboxylase gene
Several variants have been identified surrounding GAD1, the gene encoding the 67 kDa isoform of glutamate decarboxylase. These variants confer risks for childhood-onset schizophrenia [4] or are weakly associated with bipolar disorder [5]. However, there is no evidence linking single-nucleotide polymorphisms within the GAD1 coding region and genetic risk for schizophrenia or bipolar disorder [4-7].
Genetic variants in the GABA transporter gene
Variants in SLC6A1, the gene encoding the GABA transporter 1 (GAT-1), are associated with epilepsy and developmental disorders. For instance, a patient with a SLC6A1 variant encoding the S295L mutation (substitution of serine with leucine at position 295) in GAT-1 was diagnosed with childhood absence epilepsy [8]. Other SLC6A1 variants encoding for mutations in GAT-1, including W235R, F270S, and Y445C, are also associated with epilepsy [9].
Genetic variants in the GABA-A receptor genes
The GABA-A receptor is a pentameric assembly [10,11] derived from up to 19 GABR gene products [12]. In other words, the GABA-A receptor is composed of five different proteins from a selection of 19 subunits: six α (α 1-6), three β (β 1-3), three γ (γ 1-3), three ρ (ρ 1-3), and one each of the δ, ε, π, and θ subunits [13]. The subunits’ composition accounts for differences in receptor pharmacology, channel kinetics, and subcellular localization [14]. In addition, GABA-A receptors are very heterogeneous and widespread while exhibiting different spatial and temporal expression patterns in the central nervous system [15]. Mutations in the GABA-A receptor can prevent its proper activation via GABA binding, disrupt post-synaptic neurons, and alter its density on the neuronal surface, transcription, and RNA processing [16]. Variants in the genes encoding for GABA-A receptors have been found in patients with neurological diseases, including epilepsy, schizophrenia, and autism [17-21].
Epilepsy
Many variants associated with epilepsy are in the GABRA1, GABRB3, GABRG1, GABRG2, and GABRD genes, which respectively code for the α1, β3, γ1, γ2, and δ subunits of the receptor [18,19,22-24]. Some result in amino acid changes in the final protein, while others are in regions encoding the promoter or signal peptide. For instance, mutations γ2(R82Q) (substitution of arginine with glutamine at position 82 of the γ2 protein) and γ2(Q390X) result in the retention of the modified subunit in the endoplasmic reticulum. Clinically, these two mutations are found in childhood absence epilepsy/febrile seizures and generalized epilepsy with febrile seizures plus/Dravet syndrome. Mutations in the β3 subunit, including β3(P11S), β3(S15F), and β3(G32R), result in N-linked glycosylation errors and are observed in generalized epilepsy with febrile seizures plus and Dravet syndrome [25,26]. In addition, many mutations have been identified in the α1 subunit, resulting in gene deletion, protein modification, insertion, and nonsense mutations. Mutations in the α1 subunit are associated with epileptic encephalopathies, Dravet syndrome, and idiopathic epilepsies. Other GABR variants can result in the reduction of GABA-A receptor expression on the neuronal surface or an impairment of its activation, the production of truncated proteins (α1(S326fs), γ2(Q40X),γ2(Q429X) [20,27-31], mis-folded subunits (α1(A322D)) or altered channel kinetic (γ2(K328M), γ2(R177G), δ(E177A), δ(R220H)) [18,32,33].
Schizophrenia
Several variants of the GABRB2 gene have been associated with schizophrenia [34]. These single-nucleotide polymorphisms (SNPs) result in protein changes that disrupt the proper delivery of the GABA-A receptor to the neuronal surface or alter its channel kinetics. In addition, two SNPs in the GABRB2 favor the expression of a short β3 isoform subunit that is less stable than the longer one, resulting in GABA-A receptor desensitization and rundown [35,36].
Genetic variants in the GABA transaminase or succinate-semialdehyde dehydrogenase genes
The ABAT and ALDH5A1 genes encode for GABA transaminase and succinate-semialdehyde dehydrogenase, respectively. Variants in these genes have been associated with epilepsy, cognitive impairment, and succinate-semialdehyde dehydrogenase deficiency disorder [1].
Conclusion
The GABAergic system balances the neuronal excitatory and inhibitory activity and contributes to cognitive functions and emotional responses. The system involves many proteins that regulate GABA synthesis, transport, and degradation. Additionally, GABA interacts with three different receptors, demonstrating great diversity and heterogeneity patterns in the brain. Significant advances in sequencing technologies have led to the identification of many variants in genes encoding essential components of the GABAergic system, which have been linked to various diseases, including epilepsy and schizophrenia.
If you'd like to learn more about GABA and the GABAergic system, check out some of our other blogs:
References
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