GABA_A Receptor Autoantibodies Decrease GABAergic Synaptic Transmission in the Hippocampal CA3 Network

Autoimmune encephalitis associated with antibodies (Abs) against alpha 1, beta 3, and gamma 2 subunits of gamma-aminobutyric acid receptor A (GABA(A)R) represents a severe form of encephalitis with refractory seizures and status epilepticus. Reduction in inhibitory GABAergic synaptic activity is linked to dysfunction of neuronal networks, hyperexcitability, and seizures. The aim in this study was to investigate the direct pathogenic effect of a recombinant GABA(A)R autoantibody (rAb-IP2), derived from the cerebrospinal fluid (CSF) of a patient with autoimmune GABA(A)R encephalitis, on hippocampal CA1 and CA3 networks. Acute brain slices from C57BL/6 mice were incubated with rAb-IP2. The spontaneous synaptic GABAergic transmission was measured using electrophysiological recordings in voltage-clamp mode. The GABA(A)R autoantibody rAb-IP2 reduced inhibitory postsynaptic signaling in the hippocampal CA1 pyramidal neurons with regard to the number of spontaneous inhibitory postsynaptic currents (sIPSCs) but did not affect their amplitude. In the hippocampal CA3 network, decreased number and amplitude of sIPSCs were detected, leading to decreased GABAergic synaptic transmission. Immunohistochemical staining confirmed the rAb-IP2 bound to hippocampal tissue. These findings suggest that GABA(A)R autoantibodies exert direct functional effects on both hippocampal CA1 and CA3 pyramidal neurons and play a crucial role in seizure generation in GABA(A)R autoimmune encephalitis.