Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR-Ab) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a novel treatment compound, we developed an NMDAR-Ab mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of an NMDAR-specific neurosteroid, pregnenolone sulfate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.
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Funding: SKW was funded by an Epilepsy Research UK Fellowship (F3001) and Wellcome Trust Clinical Research Career Development Fellowship (216613/Z/19/Z) during this work. HP received support from the German Research Foundation (DFG; grant numbers PR1274/3-1, 4-1, 5-1) and the German Federal Ministry of Education and Research (BMBF; Connect-Generate). NG received support from the German Ministry for Education and Research (BMBF; 31P7398 and Connect-Generate), the National Multiple Sclerosis Society (NMSS; BRAVEinMS), the Wellcome Trust (208938/Z/17/Z) and the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University.