Altered functional levels of norepinephrine (NE), a CNS monoamine neurotransmitter may be important in several human neurologic disorders including the epilepsies and myoclonus. The tottering mouse is a genetic animal model exhibiting three spontaneous neurologic disorders: petit mal-like epilepsy, ataxia and an intermittent movement disorder (IMD), which is similar to some forms of human myoclonus. Hyperinnervation of noradrenergic terminal from nucleus locus coeruleus (LC) neurons, combined with elevated tissue NE concentrations in terminal fields of the LC have been observed in these mice. Previous evidence suggests that elevated NE is related to he neurologic disorders. The cerebellum is a major control circuit for the mammalian motor system. Elevation in cerebellar NE concentrations and lateratins in cerebellar morphology have been identified in these mutant mice. The overall goal of the proposed research projects is to further characterize the morphological and functional abnormalities of the cerebellar neural circuitry in the tottering mouse and research will focus on the IMDs and ataxia. The project has three Aims: 1: To analyze specific morphologic changes in the mutant mouse cerebellum. Both qualitative and quantitative morphologic studies will be carried out, using light and electron microscopy. 2: Using DSP-4, NE will be chemically depleted and the effect of NE depletion of the abnormal behaviors will be assessed. 3: To examine the functional output of cerebellar Purkinje cells using microdialysis to assess neurotransmitter release near Purkinje cells and the chemical output of Purkinje cells themselves. In addition, spontaneous firing rates or Purkinje cells and deep cerebellar nuclei cells will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08NS001681-02
Application #
2259748
Study Section
NST-2 Subcommittee (NST)
Project Start
1994-01-01
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Nahm, Sang-Soep; Tomlinson, Dana J; Abbott, Louise C (2002) Decreased calretinin expression in cerebellar granule cells in the leaner mouse. J Neurobiol 51:313-22
Abbott, L C; Bump, M; Brandl, A et al. (2000) Investigation of the role of the cerebellum in the myoclonic-like movement disorder exhibited by tottering mice. Mov Disord 15 Suppl 1:53-9
Abbott, L C; Sotelo, C (2000) Ultrastructural analysis of catecholaminergic innervation in weaver and normal mouse cerebellar cortices. J Comp Neurol 426:316-29
Lau, F C; Abbott, L C; Rhyu, I J et al. (1998) Expression of calcium channel alpha1A mRNA and protein in the leaner mouse (tgla/tgla) cerebellum. Brain Res Mol Brain Res 59:93-9
De Bartolomeis, A; Koprivica, V; Pickar, D et al. (1997) Opioidergic and dopaminergic gene expression in the caudate-putamen and accumbens of the mutant mouse, tottering (tg/tg). Brain Res Mol Brain Res 46:321-4
Abbott, L C; Isaacs, K R; Heckroth, J A (1996) Co-localization of tyrosine hydroxylase and zebrin II immunoreactivities in Purkinje cells of the mutant mice, tottering and tottering/leaner. Neuroscience 71:461-75