PDF(Pubmed)
Abstract：
Psychiatric and neurological symptoms, as well as cognitive deficits, represent a prominent phenotype associated with variable forms of autoimmune encephalitis, regardless of the neurotransmitter receptor targeted by autoantibodies. The mechanistic underpinnings of these shared major neuropsychiatric symptoms remain however unclear. Here, we investigate the impacts of patient-derived monoclonal autoantibodies against the glutamatergic NMDAR (NMDAR mAb) and inhibitory GABAaR (GABAaR mAb) signalling in the hippocampal network. Unexpectedly, both excitatory and inhibitory synaptic receptor membrane dynamics, content and transmissions are altered by NMDAR or GABAaR mAb, irrespective of the affinity or antagonistic effect of the autoantibodies. The effect of NMDAR mAb on inhibitory synapses and GABAaR mAb on excitatory synapses requires neuronal activity and involves protein kinase signalling. At the cell level, both autoantibodies increase the excitation/inhibition balance of principal cell inputs. Furthermore, NMDAR or GABAaR mAb leads to hyperactivation of hippocampal networks through distinct alterations of principal cell and interneuron properties. Thus, autoantibodies targeting excitatory NMDAR or inhibitory GABAaR trigger convergent network dysfunctions through a combination of shared and distinct mechanisms.
摘要：
精神和神经症状,以及认知缺陷，代表与自身免疫性脑炎的可变形式相关的突出表型，与自身抗体靶向的神经递质受体无关。然而，这些共同的主要神经精神症状的机制基础仍然不清楚。这里,我们研究了患者来源的单克隆抗体对海马网络中谷氨酸能NMDAR(NMDARmAb)和抑制性GABAaR(GABAaRmAb)信号传导的影响.出乎意料的是,兴奋性和抑制性突触受体膜动力学，内容和传输被NMDAR或GABAaRmAb改变，与自身抗体的亲和力或拮抗作用无关。NMDARmAb对抑制性突触的作用和GABAaRmAb对兴奋性突触的作用需要神经元活性并涉及蛋白激酶信号传导。在细胞层面,两种自身抗体都增加了主细胞输入的激发/抑制平衡。此外，NMDAR或GABAaRmAb通过主细胞和中间神经元特性的不同改变导致海马网络的过度激活。因此，针对兴奋性NMDAR或抑制性GABAaR的自身抗体通过共享和不同机制的组合触发会聚性网络功能障碍。
