부산대학교 도서관

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.
Synopsis: Patient-derived autoantibodies against the NMDA or GABAa receptor similarly alter the excitation/inhibition balance of principal hippocampal neurons. This shared pathological effect is triggered by similar and distinct mechanisms at the molecular and cellular levels.Patient-derived monoclonal autoantibodies against the NMDA (NMDAR mAb) or GABAa receptors (GABAaR mAb) alter both glutamatergic and GABAa receptor surface diffusion and synaptic transmissions in an activity- and protein kinase-dependent manner.At principal CA1 neurons, both NMDAR and GABAa mAbs increase the excitation/inhibition balance of inputs.NMDAR or GABAaR mAb triggers a hyperactivation of hippocampal networks through distinct alterations of principal cell and interneuron properties.
Patient-derived autoantibodies against the NMDA or GABAa receptor similarly alter the excitation/inhibition balance of principal hippocampal neurons. This shared pathological effect is triggered by similar and distinct mechanisms at the molecular and cellular levels.