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

Rebeca Mejias,Mei Han,Irina N Krasnova,Gareth M Thomas,Mikhail V Pletnikov,Zheng-Xiong Xi,Abby Adamczyk,Akira Sawa,Minae Niwa,Tao Wang,Jean-Lud Cadet,Richard L Huganir,Juan J Rodriguez-Gotor

doi:10.1038/s41398-020-01194-6

Abstract

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.

Highlights

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder affecting 7.2% of children[1] and 3.4% of adult populations[2]
Near complete lack of ZDHHC15 protein in hippocampus and heart of KO mice was confirmed by western blot analyses (Fig. 1D) using a custom rabbit polyclonal antibody
We found no significant differences in dopamine transporter (DAT), tyrosine hydroxylase (TH), dopamine beta hydroxylase, D1 dopamine receptor (DRD1), D2 dopamine receptor (DRD2), catechol-Omethyltransferase (COMT), or monoamine oxidase B (MAO-B) levels in striatum of zdhhc15-KO mice and wild type (WT) littermates (Fig. 5A–C; Supplementary Fig. 2A)

Summary

Introduction

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder affecting 7.2% of children[1] and 3.4% of adult populations[2]. It is characterized clinically by two core symptoms, inattention (IA) and hyperactivity–impulsivity (HI), with a high heritability at 70–80%3–6. Novelty seeking is a core dimension of temperament such as exploratory excitability and impulsivity[7]. Protein palmitoylation is a key post-translational modification characterized by a reversible addition of palmitate at specific cysteine residues. Palmitoylation can Mejias et al Translational Psychiatry (2021)11:65 impact membrane association, trafficking and intracellular localization, protein–protein interactions, enzyme activity, and stability of substrate proteins[20,21]. Palmitoylation plays important roles in normal physiology and diseases including schizophrenia, anxiety disorders, intellectual disability, cancer, mitochondrial functions, eye and heart development, and endothelial inflammation[23,24,25,26,27,28]

Methods

Results

Conclusion