Pathologic hyperactivity is observed in several neurologic disorders including Attention Deficit Hyperactivity Disorder (ADHD) and Tourette's syndrome (TS). The general goal of this research is to understand the etiology of pathologic hyperactivity by using a well-defined animal model to identify abnormal cellular events that ultimately result in the clinical manifestation of hyperactivity. We have identified the mouse mutant coloboma as a novel animal model of hyperactivity. These mice are profoundly hyperactive with locomotor activity exceeding 3 times that of their control littermates. We have demonstrated that the hyperactivity expressed by coloboma mice is clearly the result of a deletion of the Snap gene. This gene encodes SNAP-25, a neuron-specific protein that is a component of the machinery essential for docking and holding synaptic vesicles at the presynaptic membrane in readiness for Ca 2+ triggered neurotransmitter exocytosis. Although SNAP-25 is expressed in all neurons, our experiments have focused on catecholamine (dys) regulation because catecholamines are known to regulate hyperactivity in both man and animals. We have found that defects in catecholamine regulation are specific to the striatum and nucleus accumbens; norepinephrine (NE) concentrations are significantly increased while dopamine (DA) utilization is decreased. NE and DA regulation is normal in all other brain regions. The increase in NE likely contributes to the expression of locomotor hyperactivity in these mice as depletion of NE ameliorates the coloboma mouse hyperactivity. These results provide strong evidence for the hypothesis that, in this pathologic state, NE may modulate locomotor hyperactivity. The aberrant regulation of NE in this mouse model is especially relevant, as abnormalities in NE have been identified in ADHD and TS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034845-09
Application #
6984768
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (07))
Program Officer
Mamounas, Laura
Project Start
1997-06-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
9
Fiscal Year
2006
Total Cost
$379,188
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fan, Xueliang; Bruno, Kristy J; Hess, Ellen J (2012) Rodent models of ADHD. Curr Top Behav Neurosci 9:273-300
Fan, Xueliang; Xu, Ming; Hess, Ellen J (2010) D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD. Neurobiol Dis 37:228-36
Fan, Xueliang; Hess, Ellen J (2007) D2-like dopamine receptors mediate the response to amphetamine in a mouse model of ADHD. Neurobiol Dis 26:201-11
Bruno, Kristy J; Freet, Christopher S; Twining, Robert C et al. (2007) Abnormal latent inhibition and impulsivity in coloboma mice, a model of ADHD. Neurobiol Dis 25:206-16
Bruno, Kristy J; Hess, Ellen J (2006) The alpha(2C)-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder. Neurobiol Dis 23:679-88
Fureman, Brandy E; Campbell, Daniel B; Hess, Ellen J (2003) Regulation of tyrosine hydroxylase expression in tottering mouse Purkinje cells. Neurotox Res 5:521-8
Jones, Michelle D; Hess, Ellen J (2003) Norepinephrine regulates locomotor hyperactivity in the mouse mutant coloboma. Pharmacol Biochem Behav 75:209-16
Fureman, Brandy E; Jinnah, H A; Hess, Ellen J (2002) Triggers of paroxysmal dyskinesia in the calcium channel mouse mutant tottering. Pharmacol Biochem Behav 73:631-7
Jones, M D; Williams, M E; Hess, E J (2001) Abnormal presynaptic catecholamine regulation in a hyperactive SNAP-25-deficient mouse mutant. Pharmacol Biochem Behav 68:669-76
Jones, M D; Williams, M E; Hess, E J (2001) Expression of catecholaminergic mRNAs in the hyperactive mouse mutant coloboma. Brain Res Mol Brain Res 96:114-21

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