Abstract
Overall : This symposium has a translational approach. First, we present human post-mortem and in-vivo imaging studies on the pivotal role of oligedondrocyte loss and dysfunction with consecutive impairments of brain connectivity in schizophrenia. Natalya Uranova will show morphometric data on ultrastructural alterations of oligodendrocytes, myelin damage and degeneration and disturbed oligodendrocyte-axon interactions in post-mortem prefrontal white matter in schizophrenia. Adrienne Lahti will report diffusion tensor imaging data suggesting impaired axonal and myelin integrity. Because, MR Spectroscopy permits the non-invasive measurement of neurometabolites, such as N-acetylaspartate, a marker of neuronal integrity, and glutamate, which can be neurotoxic when overproduced, this technique provides further understanding of the relationship between white matter microstructure and neuronal function.Second, we present data from cell culture and animal models suggesting that restoration of oligodendrocyte function (in terms of energy metabolism, maturation and myelin production) is a promising target for the development of novel treatment strategies in schizophrenia. Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains. Lan Xiao′s lab has shown that oligodendrocyte dysfunction and impaired myelination in the prefrontal cortex is correlated with schizophrenia-like behavior in mice undergoing prolonged social isolation. Enhancing oligodendrocyte generation and myelin repair by FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) successfully reversed the above phenotype.
Highlights
The vast majority of studies of neuropsychological (NP) functioning in Clinical High Risk (CHR) cohorts have examined group averages, possibly concealing a range of subgroups ranging from very impaired to high functioning
Knowledge about the long-term cognitive course in psychotic disorders is limited. In this 18-year follow-up of participants of the Suffolk County project we report on the longitudinal course of cognitive performance in individuals with schizophrenia spectrum disorders, affective psychoses and other psychoses
Our findings indicate that cognitive functioning in psychotic disorders continues to decline after the illness onset, that this decline is not specific to schizophrenia but present across psychotic disorders, and that, relative to never-psychotic individuals, impairments on some key-cognitive domains worsen with age
Summary
While comparing the proteomes and subproteomes of 8 postmortem brain regions and cerebrospinal fluid from schizophrenia patients to controls, we consistently observed alterations in energy metabolism, cell growth and maintenance, synaptic function, and myelinization processes. Considering the nature of these analyses, it was not possible to reveal which particular cell types display such alterations. This is essential information given increasing evidence of glia cells as pivotal players in schizophrenia. With this in mind, we analyzed the proteomes and phosphoproteomes of cultured astrocytes, oligodendrocytes and neurons treated with MK-801, a NMDA-receptor antagonist which impairs glutamatergic transmission as postulated in schizophrenia. Human embryonic stem cells reprogramed from schizophrenia patients and controls fibroblasts were cultured in mTeSR1 media on Matrigel coated surface and differentiated into cerebral organoids.
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