Anti-GABAB receptor autoimmunity causes cognitive decline by presynaptic pathology
The GABAB 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 GABAB receptors causing autoimmune encephalitis with severe memory dysfunction and epilepsy. We demonstrate that human autoantibodies target the sushi-domains of the GABAB 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 GABAB receptor disturbance, synaptic pathology, circuit dysfunction, and dementia distinct from classical neurodegenerative processes.