TY  - JOUR
AU  - Wright, Sukhvir K
AU  - Rosch, Richard E
AU  - Wilson, Max A
AU  - Upadhya, Manoj A
AU  - Dhangar, Divya R
AU  - Clarke-Bland, Charlie
AU  - Wahid, Tamara T
AU  - Barman, Sumanta
AU  - Goebels, Norbert
AU  - Kreye, Jakob
AU  - Prüß, Harald
AU  - Jacobson, Leslie
AU  - Bassett, Danielle S
AU  - Vincent, Angela
AU  - Greenhill, Stuart D
AU  - Woodhall, Gavin L
TI  - Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis.
JO  - Communications biology
VL  - 4
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2021-01351
SP  - 1106
PY  - 2021
N1  - CC BY
AB  - 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.
KW  - Animals
KW  - Anti-N-Methyl-D-Aspartate Receptor Encephalitis: chemically induced
KW  - Autoantibodies: adverse effects
KW  - Disease Models, Animal
KW  - Male
KW  - Rats
KW  - Rats, Wistar
KW  - Synaptic Transmission
LB  - PUB:(DE-HGF)16
C6  - pmid:34545200
C2  - pmc:PMC8452639
DO  - DOI:10.1038/s42003-021-02635-8
UR  - https://pub.dzne.de/record/162694
ER  -