Examining and identifying function and role of LPHN3 in ADHD
Specific Aim 1: LPHN3 KO, heterozygous (HET), and WT littermates, will be comprehensively assessed for working memory-based attention, sensory-mediated attention, cognitive flexibility, impulsivity, and inhibitory control to determine the fidelity of the KO and HET rats to the symptoms of ADHD. In addition, we will determine the corrective effects of ADHD medications (methylphenidate and atomoxetine) at reducing Lphn3 KO hyperactivity. We will also confirm preliminary data of impaired caudate DA release, altered hippocampal long-term potential (LTP), and determine if the reduced prefrontal cortex (PFC) NE levels recently observed translate to impaired NE release (PFC is critical for working memory/attention).
Specific Aim 2: Develop founder Floxed Lphn3 rats. After confirming 3’ and 5’ LoxP insertions, we will breed a colony of this new line as a tool to test hypotheses about how LPHN3 disruption leads to catecholaminergic ADHD-related symptoms. Aim-2: Cross floxed Lphn3 rats with TH-Cre rats to create catecholaminergic conditional KO rats (cKO) and compare their effects to the constitutive KOs. Collectively, these experiments will provide new insights into how variant LPHN3 confers ADHD-C symptoms and provide deeper understanding of the pathophysiology of ADHD-related behavioral changes. We will use these data in support of an NIH R01 application.
Charles V. Vorhees, Ph.D.
Charles V. Vorhees, Ph.D., is Professor of Pediatric Neurology, Cincinnati Children’s Research Foundation & University of Cincinnati College of Medicine. He received his B.A. with Honors in Psychology/Biology from the University of Cincinnati and M.A. and Ph.D. in Neurobiology from Vanderbilt University. His research focuses on developmental neurological and neurocognitive deficits found in children using animal models of these disorders. His newest area of interest is in Attention Deficit Hyperactivity Disorder (ADHD) based on recent human studies linking a novel gene (Latrophilin-3) to some ADHD children. Based on this, his lab created an Lphn3 knockout rat that shows many features of ADHD. He has worked in many other areas over the years, including the prenatal effects of anticonvulsants, antidepressants, retinoids, and PCBs, and the postnatal effects of substituted amphetamines, manganese, stress, and pyrethroid insecticides. He has worked on several genetic models of developmental disorders including loss-of- function mouse models of Pde1b, Npas3, Slc6A8, Slc3010A, and Cyp1a2. He has served on advisory panels for NRC, FDA, EPA, and ILSI. He was a member of an NIH study section for 4 years and has served as ad hoc reviewer on 32 other NIH study sections. He has also served as a grant reviewer for FDA, Oak Ridge National Laboratory, EPA, Wellcome Trust, UK MRC, New Zealand, Israel, Ireland, Canada, March of Dimes, Azerbaijan, American Chemistry Council, NSF, and the VA. He is a faculty member of graduate programs in Neuroscience and in Molecular & Developmental Biology and been advisor to 15 doctoral students and 17 postdoctoral fellows. He has published >320 articles and been funded by NIH, NSF, FDA, and DOD and other organizations. He was Editor-in- Chief of Neurotoxicology & Teratology for 9 years and Section Editor for 12 years. He is a founding member of the Developmental Neurotoxicology Society and was elected as President twice. He is Co-Director of the Animal Behavior Core at Cincinnati Children’s and Director of the Teratology Training Program at Cincinnati Children’s.