Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony

Abstract

Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.

Anti-NMDAR encephalitis antibodies cause long-lasting degradation of the hippocampal neural representation of memory

“…The animal model can now be used for additional investigations on the role of NMDAR in memory maintenance and recall as well as for novel approaches (i.e., allosteric modulators of NMDA or AMPA receptors) to treat the long-term memory and behavioral alterations of the disease. 24,52…”

“…With a computational model, they showed that the transition to an ictogenesis was best explained by changes in synaptic weights that pushed excitation/inhibition out of balance. Ceanga et al 52 used in-vitro recordings and a computational model to demonstrate that changes in excitation/inhibition balance caused by lower AMPAR strength and faster GABAA-receptor kinetics, mainly accounted for the abnormal EEG oscillations. Therefore, we provide here a different set of studies focused on memory and behavior, in which we were able to link the excitation/inhibition unbalance with alterations of these tasks.…”

Comparative Effects of Domain-Specific Human Monoclonal Antibodies Against LGI1 on Neuronal Excitability

“…Curve permutation tests were performed by comparing the difference in the area under the curve of the group-averaged curves, with those obtained after shuffling the individual curves across groups, with 1 million times repetition; see Ref. 35 for more details. To statistically compare the cluster density and distance parameters between groups at proximal, middle, and distal sections, we adapted the permutation test of Cohen, thereby accounting for multiple comparison problem.…”

Mechanisms of autoimmune encephalitis

“…Using a passive transfer mouse model, the antibodies caused disrupted excitatory-inhibitory balance resulting in hippocampal CA1 neuronal hypoexcitability, reduced AMPAR signaling, and faster synaptic inhibition in acute hippocampal slices, ultimately triggering increased gamma oscillations. A positive allosteric modulator of AMPAR improved the aberrant gamma activity, suggesting a potentially novel treatment [111 ▪▪ ]. Another observation suggested that pregnenolone, a neurosteroid that upregulates NMDAR, reduced epileptic activity in brain slices from a rat passive transfer model [112].…”

“…The effects of patients’ antibodies not only induce functional and structural synaptic changes at the cellular level, but also produce important changes at the circuitry level [111 ▪▪ ,112]. Using a passive transfer mouse model, the antibodies caused disrupted excitatory-inhibitory balance resulting in hippocampal CA1 neuronal hypoexcitability, reduced AMPAR signaling, and faster synaptic inhibition in acute hippocampal slices, ultimately triggering increased gamma oscillations.…”