Work

Anti-GABA B receptor autoimmunity causes cognitive decline by presynaptic pathology

Year: 2026

Type: preprint

Abstract: Summary The GABA B receptor is a central regulator of neuronal transmission and excitability by pre- and postsynaptic mechanisms. Its dysfunction causes severe neurological disease, but the underlying pathomechanisms remain elusive. Here, we exploit a distinct CNS autoimmune disorder in which patients develop specific autoantibodies against GABA B receptors causing autoimmune encephalitis with severe memory dysfunction and epilepsy. We demonstrate that human autoantibodies target the sushi-domains of the GABA B receptor B1a subunit and the B2 subunit and interfere with presynaptic signaling. This specific presynaptic pathology results from exclusive functional antagonism of the B1a subunit and disrupts short- and long-term synaptic plasticity, abnormally amplifies hippocampal network oscillations and coupling in vivo , and ultimately impairs memory consolidation. Our results demonstrate that autoimmune presynaptic pathomechanisms alone are sufficient to interfere with memory processing, thus defining a causal link between molecular GABA B receptor disturbance, synaptic pathology, circuit dysfunction, and dementia distinct from classical neurodegenerative processes.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.22.761036