In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model

Sukhvir K Wright; Richard E Rosch; Max A Wilson; Manoj A Upadhya; Divya R Dhangar; Charlie Clarke-Bland; Tamara T Wahid; Sumanta Barman; Norbert Goebels; Jakob Kreye; Harald Prüss; Leslie Jacobson; Danielle S Bassett; Angela Vincent; Stuart D Greenhill; Gavin L Woodhall

doi:10.1101/2020.12.22.423962

In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model

Sukhvir K Wright, Richard E Rosch, Max A Wilson, Manoj A Upadhya, Divya R Dhangar, Charlie Clarke-Bland, Tamara T Wahid, Sumanta Barman, Norbert Goebels, Jakob Kreye, Harald Prüss, Leslie Jacobson, Danielle S Bassett, Angela Vincent, Stuart D Greenhill, Gavin L Woodhall

Research output: Preprint or Working paper › Preprint

Abstract

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.

Original language	English
DOIs	https://doi.org/10.1101/2020.12.22.423962
Publication status	Published - 22 Dec 2020

Bibliographical note

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

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.

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Wright, S. K., Rosch, R. E., Wilson, M. A., Upadhya, M. A., Dhangar, D. R., Clarke-Bland, C., Wahid, T. T., Barman, S., Goebels, N., Kreye, J., Prüss, H., Jacobson, L., Bassett, D. S., Vincent, A., Greenhill, S. D., & Woodhall, G. L. (2020). In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model. https://doi.org/10.1101/2020.12.22.423962

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abstract = "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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Wright, SK, Rosch, RE, Wilson, MA, Upadhya, MA, Dhangar, DR, Clarke-Bland, C, Wahid, TT, Barman, S, Goebels, N, Kreye, J, Prüss, H, Jacobson, L, Bassett, DS, Vincent, A, Greenhill, SD & Woodhall, GL 2020 'In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model'. https://doi.org/10.1101/2020.12.22.423962

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AU - Dhangar, Divya R

AU - Clarke-Bland, Charlie

AU - Wahid, Tamara T

AU - Barman, Sumanta

AU - Goebels, Norbert

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AU - Bassett, Danielle S

AU - Vincent, Angela

AU - Greenhill, Stuart D

AU - Woodhall, Gavin L

N1 - The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 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.

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N2 - 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.

AB - 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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BT - In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model

ER -

In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model

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