GENETIC STRAIN EFFECTS AND DOPAMINE CELL LOSS IN WEAVER MUTANT

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Knowledge of the mechanisms controlling nerve cell number and nerve cell loss in the brain is central to the understanding of central nervous system functions in health and disease. The evidence of differences in nerve cell number within brain regions among different strains of mice indicates that putative genes control the variability of neuronal number in discrete areas of the brain. In mice of the CBA/J strain the number of midbrain dopamine (DA) neurons in some 20% lower than in BALB/cJ mice. It is conceivable that the number of midbrain DA neurons is genetically regulated also in man. If certain individuals be endowed with a lesser number of a specific nerve cell population, say the DA cell population, would such individuals, as a result of a mutant gene, fall victim to functional deficit - Parkinson Disease - earlier? Is there a threshold? We have previously found that the single gene mutation weaver (wv) affects the viability of the midbrain DA neurons and induces a postnatal loss of these cells. In hybrid B6CBA- Aw-j/A mice, homozygous for the wv gene, the neurons of the mesotelencephalic DA system are approximately 47% fewer than in the wild type by 90 days of age. The influence of the strain-associated variability of the number of midbrain DA neurons upon the phenotypic expression of a single gene mutation affecting that neuronal population, has not been previously investigated. We intend to determine whether the percentage of DA neurons lost postnatally as an effect of the wv gene is fixed, regardless of strain, or varies in relation to the number of DA neurons with which the specific strain is originally endowed. To this end we will obtain homozygous wv mutant mice congenic in the CBA/J strain as well as in the BALB/cJ strain, will determine the number of neurons of the mesencephalic DA system in wv homozygotes and controls at maturity for each strain and will measure neurochemical dopaminergic markers in the midbrain and the striatum of mutant and wild type mice. The wv gene will be introduced in the BALB/cJ and CBA/J background using the breeding technique known as the backcross system. Thirteen backcross generations will be required to produce the congenic lines. When these will be obtained, nerve cell counts and statistical analysis of DA neurons will be carried out in the midbrain. The data will allow us to determine whether there is a relation between the strain-specific nerve cell number and the number of cells that are programmed to die as a consequence of a single gene mutation. With these studies it may be possible to extrapolate general neurobiological principles and to formulate new hypotheses to be tested studying degenerative diseases of the human brain, such as Parkinson disease.