The potential role of astroglial GABAA receptors in autoimmune encephalitis associated with GABAA receptor antibodies and seizures

Abstract

AbstractThe 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 GABAAR leads to a rapid hyperpolarization and a higher excitation threshold due to an increase in membrane Cl− permeability. The synaptic GABAAR 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 GABAAR 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 GABAAR Abs on neurons with decreased GABAergic synaptic transmission and increased neuronal excitability. The expression of GABAAR on astrocytes is well established. However, extensive studies about the effects of autoimmune GABAAR Abs on astrocytic GABAAR are missing. We hypothesize that GABAAR Abs may lead additionally to blocking astrocytic GABAARs 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 GABAAR subunits in rodent astrocytes are α1, α2, β1, β3, and γ1 localized in both white and gray matter. Data about GABAAR subunits in human astrocytes are even more limited, comprising α2, β1, and γ1. Overlapping binding of GABAAR Abs to neuronal and astroglial receptors is still possible. In vitro and in vivo animal models can be helpful to test the effects of GABAAR 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 GABAAR encephalitis with seizures.