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.
