Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model.

Yu, G; Su, Y; Guo, C; Yi, C; Yu, B; Chen, H; Cui, Y; Wang, X; Wang, Y; Chen, X; Wang, S; Wang, Q; Chen, X; Hu, X; Mei, F; Verkhratsky, A; Xiao, L; Niu, J

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model.

Yu, G Su, Y Guo, C Yi, C Yu, B Chen, H

Cui, Y Wang, X Wang, Y Chen, X Wang, S Wang, Q Chen, X Hu, X Mei, F Verkhratsky, A Xiao, L Niu, J

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Publisher:: SPRINGERNATURE
Publication Type:: Journal Article
Citation:: Mol Psychiatry, 2022, 27, (12), pp. 5154-5166
Issue Date:: 2022-12

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Field	Value	Language
dc.contributor.author	Yu, G
dc.contributor.author	Su, Y
dc.contributor.author	Guo, C
dc.contributor.author	Yi, C
dc.contributor.author	Yu, B
dc.contributor.author	Chen, H https://orcid.org/0000-0001-6883-3752
dc.contributor.author	Cui, Y
dc.contributor.author	Wang, X
dc.contributor.author	Wang, Y
dc.contributor.author	Chen, X
dc.contributor.author	Wang, S
dc.contributor.author	Wang, Q
dc.contributor.author	Chen, X
dc.contributor.author	Hu, X
dc.contributor.author	Mei, F
dc.contributor.author	Verkhratsky, A
dc.contributor.author	Xiao, L
dc.contributor.author	Niu, J
dc.date.accessioned	2023-04-18T03:50:44Z
dc.date.available	2022-09-02
dc.date.available	2023-04-18T03:50:44Z
dc.date.issued	2022-12
dc.identifier.citation	Mol Psychiatry, 2022, 27, (12), pp. 5154-5166
dc.identifier.issn	1359-4184
dc.identifier.issn	1476-5578
dc.identifier.uri	http://hdl.handle.net/10453/169925
dc.description.abstract	Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs' Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	SPRINGERNATURE
dc.relation.ispartof	Mol Psychiatry
dc.relation.isbasedon	10.1038/s41380-022-01777-3
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences
dc.subject.classification	Psychiatry
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Brain
dc.subject.mesh	Myelin Sheath
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Oligodendrocyte Precursor Cells
dc.subject.mesh	Oligodendroglia
dc.subject.mesh	Schizophrenia
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Brain
dc.subject.mesh	Oligodendroglia
dc.subject.mesh	Myelin Sheath
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Schizophrenia
dc.subject.mesh	Oligodendrocyte Precursor Cells
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Brain
dc.subject.mesh	Myelin Sheath
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Oligodendrocyte Precursor Cells
dc.subject.mesh	Oligodendroglia
dc.subject.mesh	Schizophrenia
dc.subject.mesh	Disease Models, Animal
dc.title	Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model.
dc.type	Journal Article
utslib.citation.volume	27
utslib.location.activity	England
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
utslib.for	17 Psychology and Cognitive Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.date.updated	2023-04-18T03:50:30Z
pubs.issue	12
pubs.publication-status	Published
pubs.volume	27
utslib.citation.issue	12

Abstract:

Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs' Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/169925