Anti-GABA-B autoimmune encephalitis: autoantibody-induced hippocampal pathophysiology in a murine model of the disease and future treatment strategies

In the last two decades, autoimmune encephalitis (AE) has emerged as a novel group of central nervous system disorders characterized by pathogenic autoantibodies (aAB) against synaptic antigens. More than 15 disease-defining targets have been identified, yet treatment remains limited to non-specific immunotherapies and plasmapheresis, which may require months to become effective. In anti-GABAB receptor (GABABR) AE, aAB target the GABAB receptor, a G-protein coupled receptor regulating neurotransmitter release and neuronal excitability. Patients develop epilepsy, cognitive impairment, and memory deficits, but the underlying molecular and network mechanisms are incompletely understood, and no target-specific therapies are available. This project investigates the effects of anti-GABABR aAB on hippocampal-dependent cognitive and epileptic pathways and evaluates a novel Fc-fusion construct as a therapeutic approach. Purified patient-derived anti-GABABR IgG were applied in a chronic passive-transfer mouse model to assess memory using the Novel Object Recognition test. Synaptic plasticity was examined by ex vivo field potential recordings and long-term potentiation (LTP) in CA1. Seizure susceptibility was evaluated by in vivo local field potential recordings during pentylenetetrazol-induced seizures. Super-resolution microscopy in primary neurons was used to analyze IgG binding sites and synaptic alterations. Anti-GABABR IgG impaired memory consolidation, disrupted LTP induction, altered network excitability, and exerted proconvulsive effects. IgG localized preferentially to peri-synaptic structures. Importantly, the Fc-fusion construct prevented hallmark symptoms in a related AE subtype targeting NMDA receptors. These findings provide mechanistic insight into anti-GABABR AE and support Fc-fusion constructs as a promising complementary therapeutic strategy.