By: Maddy Sanz
Introduction
Neurotransmitters are essential messengers that convert electrical energy into chemical energy, facilitating neuron communication. This intricate communication network is the cause of a myriad of essential physiological processes, such as movement, cognition, and mood (Grider, M.H., 2023). Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS), and it plays a crucial role in maintaining neural excitability and preventing overstimulation (Treiman, 2001).
Disruptions in GABA function are closely related to a multitude of neurological disorders, including epilepsy. Epilepsy is a condition distinguished by sudden, recurrent, synchronized, and excessive electrical discharges in the brain due to abnormal neuronal activity (Stratsform and Carmant, 2015). Here, we will examine the function of neurotransmitters with a focus on how dysfunction in these normally regulated processes leads to neurological disorders such as epilepsy.
Neurotransmitters and Their Function
Neurotransmitters are chemical substances released by neurons to transmit signals across synapses to other neurons, muscles, or glands. Stored in synaptic vesicles within the presynaptic neuron, neurotransmitters are released into the post synaptic cleft following an action potential; an action potential fires when the resting membrane potential is disrupted by an influx of ions and causes depolarization (making the cell more positive in charge) or hyperpolarization (making the cell more negative in charge) of the neuronal membrane (Grider, MH 2023). Once in the synaptic cleft, neurotransmitters bind to specific receptors on the postsynaptic neuron–or the “receiving” neuron–and result in either excitatory or inhibitory effects (Vaskovic, 2023). Excitatory neurotransmitters, such as Glu, depolarize the membrane, causing another action potential to fire, releasing the neurotransmitter-filled vesicles from the neuron. In contrast, inhibitory neurotransmitters such as GABA hyperpolarize the postsynaptic membrane, decreasing the likelihood of neuronal firing (van den Pol, 2012). The delicate balance between excitatory and inhibitory signals is imperative for normative brain function, and its dysfunction can lead to a plethora of neurological conditions, including epilepsy.
GABA, The Inhibitory Neurotransmitter
GABA is synthesized from one of the 20 proteinogenic amino acids– glutamate– via the enzyme glutamate decarboxylase (GAD), and is widely distributed throughout various brain regions (Treiman, 2001). It exerts its inhibitory effects via binding to GABA-A and GABA-B receptors. GABA-A receptors specifically are heteropentamers formed of 19 subunits (Treiman, 2001). Activation of these receptors via binding of GABA results in an influx of chloride ions, hyperpolarizing the neuronal membrane. This hyperpolarization has an inhibitory effect, as the neurotransmitter-bound vesicles are prevented from being released into the synaptic cleft to exert their effects (Stratsform and Carmant, 2015). How these receptors act differs in mechanism as well as in longevity. GABA-A receptors are ionotropic receptors, functioning as ligand-gated ion channels that exert their effects rapidly. GABA-B receptors, on the other hand, are metabotropic, often using G-protein-coupled receptors that influence neuronal activity through second messenger systems. Second messenger systems often result in prolonged inhibitory effects (Alexander, 2015).
GABA is also implicated in the modulation of neuronal migration, synaptogenesis, and plasticity during neurodevelopment. Disruptions in GABA activity during brain development can have long-term effects and may predispose individuals to neurological disorders such as epilepsy, autism, and schizophrenia (Ben-Ari et. al, 2007).
GABA Abnormalities in Epilepsy
In many types of epilepsy, dysfunction of the GABAergic inhibition is a central pathophysiological feature. This dysfunction can occur via multiple different mechanisms: 1. Receptor Subunit Alterations: Changes in the expression or composition of GABA-A receptor subunits are observed in epileptic brain tissue. Reduced expression of the alpha-1 and gamma-2 subunits, coupled with increased expression of the alpha-4 and delta subunits, has been noted in the hippocampus of patients with temporal lobe epilepsy, or TLE (Absalom et al., 2023). These changes shift the receptor conformation, alter receptor kinetics, and thus weaken inhibitory control.
2. GABA Transporter Dysregulation: GABA transporters (i.e., GAT-1) function as a reuptake mechanism for GABA in the synaptic cleft. GAT-1 transporters are often upregulated in epilepsy, reducing the extracellular GABA concentrations and diminishing the strength of inhibition (Coulter and Eid, 2012).
3. Gene Mutations: Mutations in genes encoding GABA-A receptor subunits (e.g., GABRG2 and GABRA1) have been implicated in childhood absence epilepsy (Macdonald et al., 2012). These deleterious mutations result in impaired receptor assembly and function, compromising inhibitory transmission.
4. Reduced GABA synthesis: GAD65 and GAD67 are two enzymes responsible for GABA synthesis; these enzymes are often downregulated in individuals with epilepsy, resulting in diminished GABA availability (Bolneo et al., 2022). This synthesis deficit further enables a hyperexcitable neural environment.
5. Interneuron Loss: The death or dysfunction of GABAergic interneurons in epileptogenic regions of the brain intensifies local disinhibition and facilitates the spread of seizure activity (Powell, 2013).
6. Reduced overall GABA concentration: Magnetic resonance spectroscopy (MRS) studies have demonstrated reduced GABA concentrations in the brains of patients with focal
epilepsy, further implicating GABA as a significant neurotransmitter involved in epilepsy (Levy et al., 2013).
These abnormalities collectively cause dysregulation of the excitatory and inhibitory pathways of the brain, fostering a hyperexcitable neuronal environment that favors the propagation of seizures.
Therapeutic Implications
Understanding the pivotal role of GABA in epilepsy has given rise to the development of therapeutic strategies aimed at enhancing GABAergic inhibition and restoring the excitatory-inhibitory balance. Both pharmacological treatments as well as innovative experimental approaches have been formulated to target the underlying mechanisms of GABAergic function.
Pharmacological therapies primarily focus on augmenting GABA transmission. Benzodiazepines act as positive allosteric modulators of GABA-A receptors and increase synaptic inhibition (Treiman, 2001). Barbiturates function similarly by prolonging the duration of chloride channel opening, thus enhancing GABA’s inhibitory effects (Treiman, 2001). Other classes of drugs aiming to alleviate epileptic seizures target GABA reuptake transporters. Tiagabine is a GABA reuptake inhibitor that selectively inhibits the GAT-1 transporter, thus reducing GABA reuptake into the presynaptic terminal and enhancing extracellular GABA availability (Madsen et al., 2011). The prolonged presence of GABA in the synaptic cleft increases inhibitory signaling and improves seizure control.
Among the most commonly prescribed AEDs (anti-epileptic drugs) for managing epilepsy, drugs such as valproate and topiramate exert their effects in a multifaceted fashion. Pharmacological mechanisms include viral delivery of GAD65 or GAD67 to boost GABA synthesis in specific brain regions (Kent et al., 1998). These drug therapies target different aspects of GABA signaling in the brain in order to reduce epileptic seizures.
Conclusion
GABA is imperative to the inhibitory control of neuronal activity, and dysfunctions in its signaling are implicated in the pathogenesis of epilepsy. Dysfunction can arise from receptor modifications, transporter expression, gene mutations, impaired synthesis, or interneuron loss. Drugs that target and enhance GABA signaling are a cornerstone of epilepsy management and continue to evolve with advances in neuroscience. Continued research into the mechanisms and intricacies of the GABAergic system offers promising avenues for more targeted and effective treatments for individuals with epilepsy.
References
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