Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice.
ATP7A
CTR1
Copper
Dysbindin
Quetiapine
Schizophrenia
Seroquel
Journal
Brain research bulletin
ISSN: 1873-2747
Titre abrégé: Brain Res Bull
Pays: United States
ID NLM: 7605818
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
26
06
2020
revised:
28
07
2020
accepted:
31
07
2020
pubmed:
17
8
2020
medline:
30
10
2021
entrez:
16
8
2020
Statut:
ppublish
Résumé
DTNBP1 gene variation and lower dysbindin-1 protein are associated with schizophrenia. Previous evidence suggests that downregulated dysbindin-1 expression results in lower expression of copper transporters ATP7A (intracellular copper transporter) and SLC31A1 (CTR1; extracellular copper transporter), which are required for copper transport across the blood brain barrier. However, whether antipsychotic medications used for schizophrenia treatment may modulate these systems is unclear. The current study measured behavioral indices of neurological function in dysbindin-1 functional knockout (KO) mice and their wild-type (WT) littermates with or without quetiapine treatment. We assessed serum and brain copper levels, ATP7A and CTR1 mRNA, and copper transporter-expressing cellular population transcripts: TTR (transthyretin; choroid plexus epithelial cells), MBP (myelin basic protein; oligodendrocytes), and GJA1 (gap-junction protein alpha-1; astrocytes) in cortex and hippocampus. Regardless of genotype, quetiapine significantly reduced TTR, MBP, CTR1 mRNA, and serum copper levels. Neurological function of untreated KO mice was abnormal, and ledge instability was rescued with quetiapine. KO mice were hyperactive after 10 min in the open-field assay, which was not affected by treatment. Dysbindin-1 KO results in hyperactivity, altered serum copper, and neurological impairment, the last of which is selectively rescued with quetiapine. Antipsychotic treatment modulates specific cellular populations, affecting myelin, the choroid plexus, and copper transport across the blood brain barrier. Together these results indicate the widespread impact of antipsychotic treatment, and that alteration of dysbindin-1 may be sufficient, but not necessary, for specific schizophrenia pathology.
Sections du résumé
BACKGROUND AND PURPOSE
DTNBP1 gene variation and lower dysbindin-1 protein are associated with schizophrenia. Previous evidence suggests that downregulated dysbindin-1 expression results in lower expression of copper transporters ATP7A (intracellular copper transporter) and SLC31A1 (CTR1; extracellular copper transporter), which are required for copper transport across the blood brain barrier. However, whether antipsychotic medications used for schizophrenia treatment may modulate these systems is unclear.
EXPERIMENTAL APPROACH
The current study measured behavioral indices of neurological function in dysbindin-1 functional knockout (KO) mice and their wild-type (WT) littermates with or without quetiapine treatment. We assessed serum and brain copper levels, ATP7A and CTR1 mRNA, and copper transporter-expressing cellular population transcripts: TTR (transthyretin; choroid plexus epithelial cells), MBP (myelin basic protein; oligodendrocytes), and GJA1 (gap-junction protein alpha-1; astrocytes) in cortex and hippocampus.
KEY RESULTS
Regardless of genotype, quetiapine significantly reduced TTR, MBP, CTR1 mRNA, and serum copper levels. Neurological function of untreated KO mice was abnormal, and ledge instability was rescued with quetiapine. KO mice were hyperactive after 10 min in the open-field assay, which was not affected by treatment.
CONCLUSIONS AND IMPLICATIONS
Dysbindin-1 KO results in hyperactivity, altered serum copper, and neurological impairment, the last of which is selectively rescued with quetiapine. Antipsychotic treatment modulates specific cellular populations, affecting myelin, the choroid plexus, and copper transport across the blood brain barrier. Together these results indicate the widespread impact of antipsychotic treatment, and that alteration of dysbindin-1 may be sufficient, but not necessary, for specific schizophrenia pathology.
Identifiants
pubmed: 32795490
pii: S0361-9230(20)30581-5
doi: 10.1016/j.brainresbull.2020.07.024
pmc: PMC7554113
mid: NIHMS1620456
pii:
doi:
Substances chimiques
Antipsychotic Agents
0
Copper Transporter 1
0
Dysbindin
0
Quetiapine Fumarate
2S3PL1B6UJ
Copper
789U1901C5
Copper-Transporting ATPases
EC 7.2.2.8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
339-349Subventions
Organisme : NIMH NIH HHS
ID : R21 MH117434
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK074038
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013148
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR048311
Pays : United States
Organisme : NIMH NIH HHS
ID : K00 MH122943
Pays : United States
Organisme : NINDS NIH HHS
ID : F99 NS105208
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH111459
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK079626
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH108867
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
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