Alterations in nigrostriatal dopaminergic function within BDNF mutant mice.

The influence of brain-derived neurotrophic factor (BDNF) upon the nigrostriatal dopaminergic system was evaluated in weanling and adult mice carrying a targeted inactivated BDNF gene. Regional specificity of this BDNF mutation was assessed by assaying catecholamine concentrations within the corpus striatum, hypothalamus, and olfactory bulbs. In weanling mice dopamine, but not norepinephrine, concentrations within the corpus striatum of homozygous mutant (-/-) mice were significantly reduced with levels being 54% that of the wild-type controls (+/+) and 49% that of the heterozygous mutant (+/-) mice. While no differences were obtained among the three genotypes for hypothalamic dopamine, norepinephrine concentrations of -/- mice were significantly lower, being 62% of +/+ mice and 49% of +/- mice. The dopamine concentrations of -/- mice within the olfactory bulb were significantly reduced (69%) compared to the +/-, but not +/+ mice. Olfactory bulb norepinephrine concentrations showed a statistically significant difference among each of the three conditions with minimal levels in -/- mice (62% of +/+ and 45% of +/-). In the adults, catecholamine concentrations were measured only in +/+ and +/- mice since -/- mice do not typically survive past 21 days. Dopamine, but not norepinephrine, concentrations within the corpus striatum were significantly increased (116%) in +/- compared to +/+ mice. No other statistically significant differences were obtained in catecholamine concentrations within the hypothalamus or olfactory bulb in these adult mice. These results show that homozygous BDNF mutations produce severe depletions within the nigrostriatal dopaminergic system and substantial reductions of norepinephrine within the hypothalamus and olfactory bulb. Interestingly, maximal catecholamine concentrations for all areas sampled at both ages were observed in the +/- mice. These latter findings may indicate some subtle changes in catecholamine functions resulting from a heterozygous BDNF mutation.