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Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice.

Abstract：

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.

journal_name

Brain Res Bull

journal_title

Brain research bulletin

authors

Schoonover KE,McMeekin LJ,Farmer CB,Varghese NE,Queern SL,Lapi SE,Cowell RM,Roberts RC

doi

10.1016/j.brainresbull.2020.07.024

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

339-349

eissn

0361-9230

issn

1873-2747

pii

S0361-9230(20)30581-5

journal_volume

164

pub_type

杂志文章

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Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice.