The applicant has recently identified the mouse mutant coloboma as a novel animal model of hyperactivity with locomotor activity exceeding 3 times control mice. She has demonstrated that the hyperactivity expressed by coloboma mice is the result of a deletion of the Snap gene. This gene encodes SNAP-25, a neuron-specific protein found in presynaptic nerve terminals that plays a major role in transmitter release. SNAP-25 is a component of the machinery essential for docking and holding synaptic vesicles at the presynaptic membrane in readiness for Ca2+ triggered transmitter exocytosis. Thus, it is though likely that defects in transmitter release cause by a reduction in SNAP- 25 expression results in the expression of hyperactivity. In fact, there appears to be a dopaminergic component to the hyperactivity as the applicant has also identified gross behavioral abnormalities in response to dopamimetics. It is hypothesized that abnormalities in vesicular function result in an increased concentration of cytosolic dopamine leading the unregulated nonexocytotic dopamine release ultimately expressed as hyperactivity. This proposal focuses on Ca2+ mediated transmitter release and dopaminergin function in coloboma mice to isolate the synaptic events giving rise to hyperactivity.
The specific aims are: 1) To define abnormalities in vesicular neurotransmitter release. Individual release events will be recorded and drug-induced alterations in release assessed. 2) To assess the contribution of catecholaminergic neurotransmission to the generation of locomotor hyperactivity in coloboma mice. This contribution will be tested through a transgenic rescue experiment by replacing SNAP-25 in only catecholaminergic cells. 3) To identify neurochemical defects in vivo underlying hyperactivity in coloboma mice. These experiments will integrate the cellular defects identified in vitro with a functional analysis in vivo. 4) To determine the cellular mechanisms involved in hyperactivity using classical behavior pharmacology. Using drugs known to affect presynaptic dopamine terminals, including storage, synthesis and release, we will establish a direct link between dopamine terminal dysfunction and hyperactivity via this in vivo assay. The mouse mutant coloboma represents an unprecedented model in which to study the contributions of a single known gene to a complex multifactorial phenotype in humans which includes disorders such as attention deficit hyperactivity disorder and Tourette syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034845-02
Application #
2703080
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Broman, Sarah H
Project Start
1997-06-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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
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; Campbell, Daniel B; Hess, Ellen J (2003) Regulation of tyrosine hydroxylase expression in tottering mouse Purkinje cells. Neurotox Res 5:521-8
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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