Norepinephrine metabolism in the cerebellum of the purkinje cell degeneration (pcd) mutant mouse

Abstract

Norepinephrine (NE) metabolism in brain regions was studied in the Purkinje cell degeneration (pcd) mutant mouse. The Purkinje cells, which are target cells for noradrenergic (NA) neurons, degenerate completely in the pcd mutant mouse between 17 and 45 days of age, but the NA terminals remain intact. The purpose of this study was to determine if cerebellar NE turnover is altered after Purkinje cell loss. The concentrations of NE and of its major metabolite in mouse brain, 3-methoxy-4-hydroxy-phenylglycol (MHPG) were measured by liquid chromatography with electrochemical detection. The concentration of MHPG and the concentration ratio MHPG/NE were taken as indices of NE turnover. Although the cerebellar content of NE in the pcd mice was not different from control mice, MHPG and the ratio MHPG/NE were decreased slightly in 3-month old, and more in 6 and 9-month old, mutants compared to controls. No decrease in MHPG content or in the MHPG/NE ratio was detectable in younger mutants (22 or 45-day old). The accumulation of dopa (3,4-dihydroxyphenylalanine) after administration of NSD 1015 to inhibit aromatic l-amino acid decarboxylase was determined as an index of NE synthesis. Dopa accumulation was decreased in cerebellum to 69%, 53% and 37% of control values, respectively, at 3, 6 and 12 months in pcd mice, but was not changed in brain stem and was only slightly decreased in hypothalamus. No decrease in MHPG (content or concentration) or in the ratio MHPG/NE was found in brain stem. In hypothalamus, NE concentration and content were slightly increased in pcd mice at all ages, and the ratio MHPG/NE was decreased in 6 and 9-month old mice. We conclude that although NA axons in the cerebellum are maintained in pcd mice after Purkinje cell degeneration, NE turnover is decreased, suggesting that the synthesis and release of neurotransmitter does not continue at normal rates when the target cells have degenerated.