SELENOT regulates endoplasmic reticulum calcium flux via SERCA2 and maintains dopaminergic DAT to protect against attention deficit hyperactivity disorder in mice
bioRxiv (Cold Spring Harbor Laboratory)(2023)
摘要
Attention deficit and hyperactivity disorder (ADHD) is a prevalent developmental disorder. SELENOT is an endoplasmic reticulum-resident selenocysteine-containing protein. We aimed to investigate the role of SELENOT in dopaminergic neurons. Results from Selenotfl/fl;Dat-cre mice showed that SELENOT deficiency in dopaminergic neurons resulted in ADHD-like behaviors including hyperlocomotion, recognition memory deficit, repetitive movement, and impulsivity. Dopamine metabolism, extrasynaptic dopamine, spontaneous excitatory postsynaptic currents in the striatum and electroencephalogram theta power were enhanced in Selenotfl/fl;Dat-cre mice, whereas dopaminergic neurons in the substantia nigra were slightly reduced but exhibited normal neuronal firing and little cellular stress. Among dopamine- associated proteins, dopamine transporter (DAT) level was remarkably reduced and monoamine oxidase A increased mildly in the striatum and/or midbrain of Selenotfl/fl;Dat-cre mice. The ADHD-like phenotype and DAT ablation were corroborated in Selenotfl/fl;Nestin- cre mice, but not in Selenotfl/fl;Gfap-cre mice. In vitro overexpression and knockdown analyses and RNA-sequencing data revealed that SELENOT causatively regulated DAT mRNA and protein expression through Ca2+ signaling and NURR1. SELENOT maintained cellular Ca2+ levels via interaction with endoplasmic reticulum SERCA2, but not IP3Rs and RYRs, as demonstrated by Ca2+ imaging, co-immunoprecipitation coupled with mass spectrometry, and colocalization analyses. Treatment with psychostimulants, amphetamine or methylphenidate, rescued the hyperactivity in Selenotfl/fl;Dat-cre mice. In conclusion, SELENOT in dopaminergic neurons is indispensable to maintain proper dopamine signaling in the midbrain against ADHD.
### Competing Interest Statement
The authors have declared no competing interest.
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关键词
endoplasmic reticulum calcium flux,attention deficit hyperactivity disorder,serca2,dopaminergic dat
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