Abstract
Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) 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 potential treatment compound, we developed an NMDAR antibody 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 a neurosteroid, pregnenolone sulphate, 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.
Highlights
Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of N-methyl-Daspartate receptor (NMDAR) proteins thereby causing internalization and a state of NMDAR hypofunction
Animals were sacrificed at this time-point and brain slices were prepared for in vitro electrophysiology studies. These hippocampal local field potential (LFP) recordings showed significantly more frequent spontaneous epileptiform activity in NMDAR antibody injected slices compared to slices prepared from control antibody injected animals (Fig. 1a–d)
Using whole-cell patch clamp recordings of spontaneous excitatory post-synaptic current (sEPSC) from untreated Wistar rat hippocampal slices we showed that Pregnenolone sulphate (PregS) significantly increased amplitude and frequency of sEPSCs; the increased frequency was reversed by application of the NMDAR antagonist MK801 confirming NMDAR mediated effect (Supplementary Fig. 2a–d)
Summary
Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) 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. In vitro application of a neurosteroid, pregnenolone sulphate, 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. Both in vivo and in vitro studies have clearly established that the pathogenic action of antibodies in N-methyl-Daspartate receptor (NMDAR) antibody encephalitis is to bind to the surface of the NMDARs, cross-link the proteins and cause NMDAR internalization, resulting in a state of NMDAR hypofunction[1,2,3]. In vivo, and in silico approaches we have demonstrated that, counterintuitively, the epileptic dynamics emerge from reductions in excitatory neurotransmission caused by NMDAR antibodies, and provide proof-of-concept in vitro evidence of a NMDAR specific neurosteroid rescue treatment both in the rodent model, and in human epileptic brain tissue
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