Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder with a prevalence of 3- 7% in school-aged children and 4% in adults worldwide. Psychostamulants are extensively used for treatment of ADHD symptoms with a favorable response. However, variable clinical effectiveness, non- responsiveness and tolerance to standard treatment regimens, and increasing risks for drug abuse and mental illnesses later in life continue to be serious concerns. Dysregulations of striatal dopamine (DA) system in ADHD are widely supported by clinical, genetic, and brain imaging studies in humans and animal models, and by clinical effectiveness of psychostimulants. Despite decades of research, the precise neurobiological mechanisms for ADHD remain poorly understood, which severely hampers the development of novel, safe, and effective therapies. Palmitoylation is a reversible lipid post-translational modification catalyzed by a family of DHHC-domain palmitoyltransferases. We have generated a line of DHHC15-knockout mice that show hyperactivity and reduced DA levels in striatum. Hyperactivity in the mutant mice is responsive to amphetamine, DAT inhibitor and DA receptor inverse agonist suggesting a specific involvement of striatal DA system. We hypothesize that these ADHD-related phenotype are caused by defects in palmitoylation of one or more DHHC15 substrates in striatum. In this study, we propose to identify dhhc15 in vivo substrates in striatum using functional assays and proteomics, and to characterize the underlying neurobiological mechanisms. Results shall provide valuable insights into a novel regulatory mechanism of DA in striatum and help to identify drug targets for rational development of effective therapies for ADHD.
