Hyperactivity is associated with several human neurological disorders, such as attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). The coloboma mouse represents a model of spontaneous hyperactivity. Coloboma mice have a heterozygous, semidominant deletion mutation on mouse chromosome 2 that spans the Snap gene and causes a 50% reduction in SNAP-25 (synaptosomal-associated protein). SNAP-25 is a presynaptic docking protein that regulates exocytotic neurotransmitter release. Therefore, it is likely that presynaptic mechanisms are responsible for the hyperactivity of coloboma mice. In fact, presynaptic dopamine (DA) regulation is thought to play a major role in hyperactivity disorders. Dopaminergic abnormalities in patients who have such disorders have been studied intensively for several decades. However, it is becoming increasingly clear that norepinephrine (NE) also plays a role. The majority of drugs efficacious in the treatment of ADHD modify both DA and NE neurotransmission. Indeed, administration of clonidine, an a2-adrenergic receptor agonist that inhibits NE release, ameliorates symptoms in some ADHD and TS patients. Studies of coloboma mice also implicate NE in hyperactive behavior. Coloboma mice have high levels of NE in the striatum and nucleus accumbens, brain regions implicated in movement and attention, respectively. Destruction of noradrenergic terminals with neurotoxin DSP-4 decreases locomotor activity of coloboma mice. Thus, coloboma mice may be extremely useful for determining the role of NE in the regulation of hyperactivity. We hypothesize that aberrant neurotransmission of NE contributes to the hyperactivity of these mice.
The specific aims of this proposal are 1) to determine if noradrenergic challenge will ameliorate the coloboma phenotype, and 2) to determine the effect of drug challenge on neurotransmitter release.
|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|