GABAA receptors in epilepsy: Elucidating phenotypic divergence through functional analysis of genetic variants.

Normal brain function requires a tightly regulated balance between excitatory and inhibitory neurotransmissions. γ-Aminobutyric acid type A (GABAA ) receptors represent the major class of inhibitory ion channels in the mammalian brain. Dysregulation of these receptors and/or their associated pathways is strongly implicated in the pathophysiology of epilepsy. To date, hundreds of different GABAA receptor subunit variants have been associated with epilepsy, making them a prominent cause of genetically linked epilepsy. While identifying these genetic variants is crucial for accurate diagnosis and effective genetic counselling, it does not necessarily lead to improved personalised treatment options. This is because the identification of a variant does not reveal how the function of GABAA receptors is affected. Genetic variants in GABAA receptor subunits can cause complex changes to receptor properties resulting in various degrees of gain-of-function, loss-of-function or a combination of both. Understanding how variants affect the function of GABAA receptors therefore represents an important first step in the ongoing development of precision therapies. Furthermore, it is important to ensure that functional data are produced using methodologies that allow genetic variants to be classified using clinical guidelines such as those developed by the American College of Medical Genetics and Genomics. This article will review the current knowledge in the field and provide recommendations for future functional analysis of genetic GABAA receptor variants.

The Synthesis and Evaluation of Fluoro-, Trifluoromethyl-, and Iodomuscimols as GABA Agonists.

Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABAA receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (α1 ß2 γ2 ) and extrasynaptic (α4 ß2 γ) GABAA receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (α4 ß2 γ) receptor.