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The potential role of astroglial GABA A receptors in autoimmune encephalitis associated with GABA A receptor antibodies and seizures.

Epilepsia Open 2023 April 21
The γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system and GABA receptors mediate the inhibitory synaptic transmission. GABA binding to neuronal GABAA R leads to a rapid hyperpolarization and a higher excitation threshold due to an increase in membrane Cl- permeability. The synaptic GABAA R is mostly composed of two α(1-3), two β, and one γ subunit with the most abundant configuration α1β2γ2. Recently, antibodies (Abs) against α1, β3, and γ2 subunits of GABAA R were detected in a severe form of autoimmune encephalitis with refractory seizures, status epilepticus, and multifocal brain lesions, affecting gray and white matter. Experimental studies confirmed multiple mechanisms and direct functional effects of GABAA R Abs on neurons with decreased GABAergic synaptic transmission and increased neuronal excitability. The expression of GABAA R on astrocytes is well established. However, extensive studies about the effects of autoimmune GABAA R Abs on astrocytic GABAA R are missing. We hypothesize that GABAA R Abs may lead additionally to blocking astrocytic GABAA Rs with impaired Ca2+ homeostasis/spreading, astrocytic Cl- imbalance, dysfunction of astrocyte-mediated gliotransmission (e.g., decreased adenosine levels) and accumulation of excitatory neurotransmission, all this contributing to seizures, variable clinical/MRI presentations, and severity. The most abundant expressed GABAA R subunits in rodent astrocytes are α1, α2, β1, β3, and γ1 localized in both white and gray matter. Data about GABAA R subunits in human astrocytes are even more limited, comprising α2, β1, and γ1. Overlapping binding of GABAA R Abs to neuronal and astroglial receptors is still possible. In vitro and in vivo animal models can be helpful to test the effects of GABAA R Abs on glia. This is from an epileptological point of view relevant because of the increasing evidence, confirming the glial involvement in the pathogenesis of epilepsy. Taken together, autoimmune disorders are complex and multiple mechanisms including glia could contribute to the pathogenesis of GABAA R encephalitis with seizures.

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