Selective Prenatal Dopamine Damage in Non Human Primates

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Several brains disorders with onset before adulthood are thought to involve irregularities in the development of midbrain dopamine neurons. These include some dystonias, LeschNyhan disease, schizophrenia, and developmental hypoxicischemic injury. As relatively little is known about the ontogeny of primate dopamine neurons, the goal of this proposal is to advance understanding of the early development of these neurons, and the effects and compensations that occur in response to their selective damage. Initial studies will use normal African green monkey fetuses which will span in age from the time just after differentiation of dopamine neurons to the time just before birth. The assays performed will provide data regarding possible critical times in development in which damage to dopamine systems might have longlasting deleterious effects, including periods of natural cell death (apoptosis) in dopamine neurons and synaptogenesis of dopamine neurons with postsynaptic targets. Subsequently, the neurochemically specific protoxin, M11rP, will be given to pregnant monkeys at these times. Fetuses that are exposed to MPTP during a peak of programmed cell death may mimic situation where exaggerated or abnormal natural cell death occurs in dopamine neurons. Other fetuses will be exposed to the effects of MPTP over a substantial proportion of the gestation period, incorporating an extended period of synaptogenesis, which may mimic situations where there are fewer than normal dopamine neurons, or where there are deficits in outgrowth or synapse formation. In humans such developmental abnormalities may occur as a result of genetics, drug abuse, environmental toxins, physical trauma, anoxia or infection. Postmortem measurements in monkey fetuses will include biochemical assays of dopamine neuron number, integrity and function, and will be made just prior to birth. Subsequently we plan to examine the brains of neonates which have been exposed to MPTP in utero, when have reached 6 months of age. In the latter group, behavioral observations and a challenge with Ldopa, will also be carried out to indicate whether the infants show deficits that compromise their survival, and identify potential abnormalities for more detailed behavioral and psychological studies which would need to follow later. We are hopeful that these studies will provide insight into both the normal development of primate dopamine neurons, and their response to injury at critical times in ontogeny. Thus, the proposed work may lead ultimately to an animal model for one or more pediatric brain disorders.