神经科学
AMPA受体
NMDA受体
谷氨酸的
抑制性突触后电位
兴奋性突触后电位
海马结构
加巴能
生物
神经传递
突触可塑性
谷氨酸受体
受体
生物化学
作者
Mihai Ceangă,Vahid Rahmati,Holger Haselmann,Lars Schmidl,Daniel Hunter,Anna-Katherina Brauer,Sabine Liebscher,Jakob Kreye,Harald Prüß,Laurent Groc,Stefan Hallermann,Josep Dalmau,Alessandro Ori,Manfred Heckmann,Christian Geis
出处
期刊:Cell Reports
[Elsevier]
日期:2023-10-01
卷期号:42 (10): 113166-113166
被引量:11
标识
DOI:10.1016/j.celrep.2023.113166
摘要
Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction. After passive transfer of patients' cerebrospinal fluid or human monoclonal anti-GluN1-autoantibodies in mice, we find a disrupted excitatory-inhibitory balance resulting from CA1 neuronal hypoexcitability, reduced AMPA receptor (AMPAR) signaling, and faster synaptic inhibition in acute hippocampal slices. Functional alterations are also reflected in widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. NMDAR-Abs amplify network γ oscillations and disrupt θ-γ coupling. A data-informed network model reveals that lower AMPAR strength and faster GABAA receptor current kinetics chiefly account for these abnormal oscillations. As predicted in silico and evidenced ex vivo, positive allosteric modulation of AMPARs alleviates aberrant γ activity, reinforcing the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-Ab-induced aberrant synaptic, cellular, and network dynamics provide conceptual insights into NMDAR-Ab-mediated pathomechanisms and reveal promising therapeutic targets that merit future in vivo validation.
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