Disturbed Oligodendroglial Maturation Causes Cognitive Dysfunction in Schizophrenia: A New Hypothesis

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Citações na Scopus
4
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Dimensions
Título da Revista
ISSN da Revista
Título do Volume
Editora
OXFORD UNIV PRESS
Autores
FALKAI, Peter
ROSSNER, Moritz J.
RAABE, Florian J.
WAGNER, Elias
KEESER, Daniel
MAURUS, Isabel
ROELL, Lukas
CHANG, Emily
SEITZ-HOLLAND, Johanna
SCHULZE, Thomas G.
Citação
SCHIZOPHRENIA BULLETIN, v.49, n.6, p.1614-1624, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background and Hypothesis Cognitive impairment is a hallmark of schizophrenia, but no effective treatment is available to date. The underlying pathophysiology includes disconnectivity between hippocampal and prefrontal brain regions. Supporting evidence comes from diffusion-weighted imaging studies that suggest abnormal organization of frontotemporal white matter pathways in schizophrenia. Study Design Here, we hypothesize that in schizophrenia, deficient maturation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes substantially contributes to abnormal frontotemporal macro- and micro-connectivity and subsequent cognitive deficits. Study Results Our postmortem studies indicate a reduced oligodendrocyte number in the cornu ammonis 4 (CA4) subregion of the hippocampus, and others have reported the same histopathological finding in the dorsolateral prefrontal cortex. Our series of studies on aerobic exercise training showed a volume increase in the hippocampus, specifically in the CA4 region, and improved cognition in individuals with schizophrenia. The cognitive effects were subsequently confirmed by meta-analyses. Cell-specific schizophrenia polygenic risk scores showed that exercise-induced CA4 volume increase significantly correlates with OPCs. From animal models, it is evident that early life stress and oligodendrocyte-related gene variants lead to schizophrenia-related behavior, cognitive deficits, impaired oligodendrocyte maturation, and reduced myelin thickness. Conclusions Based on these findings, we propose that pro-myelinating drugs (e.g., the histamine blocker clemastine) combined with aerobic exercise training may foster the regeneration of myelin plasticity as a basis for restoring frontotemporal connectivity and cognition in schizophrenia.
Palavras-chave
oligodendrocytes, oligodendrocyte precursor cells, myelination, cognition, hippocampus, prefrontal cortex
URI
https://observatorio.fm.usp.br/handle/OPI/59258
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