Fundamental Neurochemistry Review: GABA_A receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy

Abstract

Epilepsy is a common neurological disorder associated with alterations of excitationinhibition balance within brain neuronal networks. GABA A receptor neurotransmission is the most prevalent form of inhibitory neurotransmission and is strongly implicated in both the pathophysiology and treatment of epilepsy, serving as a primary target for antiseizure medications for over a century. It is now established that GABA exerts a multifaceted influence through an array of GABA A receptor subtypes that extends far beyond simply negating excitatory activity. As the role of GABA A neurotransmission within inhibitory circuits is elaborated, this will enable the development of precision therapies that correct the network dysfunction underlying epileptic pathology.

An Update on Stiripentol Mechanisms of Action: A Narrative Review

“…2 a) [ 3 , 20 ]. GAT1 and GAT3 are the main GABA transporters expressed in the brain [ 24 ]. An ex vivo study found that STP does not interact with GAT1 in hippocampal neurons, suggesting the inhibition of another, unidentified, GAT subtype [ 25 ].…”

Inhibitory Synaptic Influences on Developmental Motor Disorders

“…Actions of GABA-A receptors are not uniform, with certain subtypes responsible for the synaptic fast acting phasic inhibition, with other subtypes mostly found in extrasynaptic tonically acting receptors [ 78 , 79 ]. The major subunit types of GABA-A receptors are the α, β, γ and δ, with each synaptic GABA-A receptor isoform a pentameric combination of subunits, with the majority containing two pairs of α/β dimers and one other subunit, usually γ [ 80 ] ( Figure 2 ).…”

“…Different GABA-A subtypes comprising different receptor subunit and splice variants exhibit marked pharmacological and pharmacokinetic variances. The major dimer α/β combination binds GABA [ 79 , 80 ], while the α/γ site binds GABA allosteric modulators such as benzodiazepines [ 81 , 82 ] (discussed later). Each subunit exhibits splice variants [ 80 ]; however, in homogenized mouse brain the majority of synaptic GABA-A receptors are α 1 β 2 γ 1 [ 80 , 83 ], although α 2 combinations more prevalent in the spinal cord [ 84 ] and MNs [ 85 ], with further complexity of isoforms likely to be evident during development.…”

“…Each subunit exhibits splice variants [ 80 ]; however, in homogenized mouse brain the majority of synaptic GABA-A receptors are α 1 β 2 γ 1 [ 80 , 83 ], although α 2 combinations more prevalent in the spinal cord [ 84 ] and MNs [ 85 ], with further complexity of isoforms likely to be evident during development. Extrasynaptic GABA-A receptors include a δ subunit, often with an α 4 or α 6 , which have higher affinities to GABA compared to other α/β dimers [ 79 ] ( Figure 2 ). In the hippocampus, extrasynaptic α 5 subunits are involved in tonic inhibition and may also redistribute to synaptic areas in an activity-dependent manner [ 86 ].…”

Modern Principles in the Treatment of Epilepsy

“…Важную роль в ходе возникновения эпилептических приступов играет нарушение ГАМК-ергической передачи, а именно влияние через подтипы ГАМКA рецепторов. Уточнение роли нейротрансмиссии ГАМКA в тормозных цепях позволит разработать прецизионные методы лечения, которые устраняют дисфункцию, лежащую в основе эпилептической патологии [3]. В клинической разработке находятся препараты, являющиеся положительными аллостерическими модуляторами рецепторов ГАМКА, куда относятся ENX-101, алпразалам, нейростероиды ETX 155 и LPCN 2101; препарат буметанид, а также инновационные методы лечения: ГАМК-ергические интернейроны, применение антисмыслового олигонуклеотида STK-001.…”