Periodic Reporting for period 1 - NanoPSYCH (Neuropsychiatric disorders are a heterogeneous group of mental pathologies that demand prolonged and treatments that are frequently ineffective. Elucidating the cellular and molecular mechanisms under)
Reporting period: 2019-06-01 to 2021-05-31
Neuropsychiatric disorders are a heterogeneous group of mental pathologies that demand prolonged treatments that are frequently ineffective. They represent the greatest health burden to Europe and are a priority in The European Commission’s agenda. Thus, elucidating the cellular and molecular mechanisms underlying these diseases is paramount for a precise classification of subgroups of patient and application of appropriate therapeutic strategies. The role of the immune system in the pathophysiology of neuropsychiatric disorders has been the subject of debate for many decades, and the recent recognition of antibody-mediated central nervous system (CNS) disorders has fueled the search for a subgroup of patients with an antibody-mediated psychiatric illnesses. CNS autoantibodies have demonstrated to be pathogenic by disrupting the functional or structural integrity of synapses and their study has become an exciting research topic. Several aspects about the mode of action of these pathogenic autoantibodies remain unsolved, such as their accumulation in specific brain regions. An important factor for this preferential retention could be the influence of brain extracellular space (ECS), a vital component of the brain that has remained largely inaccessible for exploration due to its complex organization and technical limitations for its examination in living tissue. Recent advances in Nanotechnology and Biotechnology have given rise to unique tools to tackle the study of complex biological systems, thus we are now in a privileged position to explore the architecture of the ECS and the dynamics of CNS autoantibodies into brain tissue. The aim of this project is to define how the dynamics of CNS autoantibodies is affected by the ECS architecture in specific brain regions. This goal will be accomplished by using an original strategy combining classical imaging approaches to map the distribution of CNS autoantibodies between different brain structures and nanoparticle monitoring strategies to visualize at the nanoscopic scale the dynamics of CNS autoantibodies and the ECS architecture.
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.
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.
This project has contributed with novel information at multiple levels. We have provided, for the first time, keystone evidence about the brain distribution of CNS autoantibodies from psychotic patients in vivo and greatly increased the understanding about autoimmune encephalopathies from a dynamic perspective.
Also, we have expanded the current knowledge about the ECS in native brain tissue and we have shed light over the mechanisms and putative factors that promote accumulation of pathogenic molecules in certain cerebral regions. Altogether, it could suppose a quantum leap in neuropsychiatry, providing a mechanistic basis underlying the onset of psychosis and schizophrenia.
At a methodological level, we have presented an original and innovative approach to test the nanoscale behavior of human autoantibodies in living tissue and in 3D. This will be a step forward in comparison with the existing murine models.
This information generate in this project can also have implications in other fields. One of them is the use of antibodies in the brain with therapeutics purposes, either like drug delivery systems or agents to clear toxic protein species (e.g. in neurodegeneration). The new and original data on the effect of the brain ECS on antibody behavior could be beneficial to optimize the delivery of these molecules inside the CNS.
Also, we have expanded the current knowledge about the ECS in native brain tissue and we have shed light over the mechanisms and putative factors that promote accumulation of pathogenic molecules in certain cerebral regions. Altogether, it could suppose a quantum leap in neuropsychiatry, providing a mechanistic basis underlying the onset of psychosis and schizophrenia.
At a methodological level, we have presented an original and innovative approach to test the nanoscale behavior of human autoantibodies in living tissue and in 3D. This will be a step forward in comparison with the existing murine models.
This information generate in this project can also have implications in other fields. One of them is the use of antibodies in the brain with therapeutics purposes, either like drug delivery systems or agents to clear toxic protein species (e.g. in neurodegeneration). The new and original data on the effect of the brain ECS on antibody behavior could be beneficial to optimize the delivery of these molecules inside the CNS.