This study was focused on a particular type of autoimmune molecules targeting the Central Nervous System (CNS), the autoantibodies against the NMDA receptor (NMDAR-Abs). This receptor has a central role in the CNS by regulating synaptic plasticity, is critical in learning and memory and is broadly accepted that the NMDAR-Abs can induce psychiatric manifestations. Indeed, over the last decade a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins - called autoimmune encephalopathies - has emerged and the most frequent and best characterized form of encephalitis is the one targeting NMDAR through NMDAR-Abs. Thus, these autoantibodies are useful tools to examine molecular and cellular aspects of the pathophysiology of psychosis.
In this proposal, we used a unique combination of recently developed single nanoparticle tracking and super-resolution microscopy approaches to unravel how NMDAR autoantibodies (from schizophrenic and encephalitis patients) navigate through the extracellular space (ECS) and decrypted why these pathogenic molecules concentrate in specific brain regions.
Specifically, we reported that the ECS nanoscale dimensions strongly differ between areas of the rodent hippocampus (a structure involved in learning and memory formation). Moreover, human pathogenic immunoglobulins directed against the NMDA receptors also displayed distinct ECS dynamics and retention within these areas. We elucidated that the ECS architecture of the hippocampus possess specific traits that favors NMDAR-Abs local retention and subsequent disturbance of their neuronal targets. We also found out that some features of the autoantibodies could account for their accumulation in the mentioned areas. We thus unveiled, at the nanoscale, that the ECS highly varies within hippocampal areas, impacting molecular dynamics and likely network pathophysiology.
These results were achieved by accomplishing these specific objectives, as follow:
1) by mapping the brain distribution of NMDAR-Abs from psychotic and encephalitis patients in living tissue
2) by tracking the dynamic behavior of NMDAR-Abs at nanoscale level in various brain areas
3) by mapping the ECS dimensions and rheology in brain regions of NMDAR-Abs aggregation
4) by testing the role of the ECS architecture in the regional retention of NMDAR-Abs
5) by evaluating the contribution of IgG particularities in the local retention of NMDAR-Abs
The information derived from this proposal is expected to be published in early 2022 in Neuron, one of the most influential and relied upon journals in the field of neuroscience. The authors of the manuscript will send a communication to the Project Officer upon submission.
