Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice

被引：15

作者：

Mejias, Rebeca ^{[1
,2
,3
]}

Rodriguez-Gotor, Juan J. ^{[3
]}

Niwa, Minae ^{[4
,5
]}

Krasnova, Irina N. ^{[6
,7
]}

Adamczyk, Abby ^{[1
,2
]}

Han, Mei ^{[1
,2
]}

Thomas, Gareth M. ^{[8
,9
]}

Xi, Zheng-Xiong ^{[10
]}

Huganir, Richard L. ^{[11
,12
]}

Pletnikov, Mikhail, V ^{[4
,11
]}

Sawa, Akira ^{[13
,14
,15
,16
]}

Cadet, Jean-Lud ^{[10
]}

Wang, Tao ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[3] Univ Seville, Dept Physiol, Seville 41012, Spain

[4] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA

[5] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35233 USA

[6] NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA

[7] NIGMS, Div Res Capac Bldg, NIH, DHHS, Bethesda, MD 20892 USA

[8] Temple Univ, Dept Anat & Cell Biol, Philadelphia, PA 19140 USA

[9] Temple Univ, Shriners Hosp, Pediat Res Ctr, Philadelphia, PA 19140 USA

[10] NIDA, Intramural Res Program, Baltimore, MD 21224 USA

[11] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, Zanvyl Krieger Sch Arts & Sci, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA

[13] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[15] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[16] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA

来源：

TRANSLATIONAL PSYCHIATRY | 2021年 / 11卷 / 01期

关键词：

ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; PROTEIN PALMITOYLATION; PERSONALITY-TRAITS; NUCLEUS-ACCUMBENS; SUBSTANCE-ABUSE; RECEPTOR GENE; TEMPERAMENT; NEURONS; ADHD;

D O I：

10.1038/s41398-020-01194-6

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

引用

页数：13