In spite of the prevalence of dyskinetic cerebral palsy (CP), little is known of its neurochemical or neuroanatomical correlates. Little is known of the neural basis for dystonia, the predominant and most disabling movement disorder of CP. The goal of this proposal is to investigate by morphologic and biochemical means the effect of perinatal hypoxia- ischemia on striatal neurotransmitter systems in a rodent model. The proposal will focus on the striatum, because the human pathologic correlate of dyekinetic CP is striatal neuron loss. The proposal will focus on striatal cholinergic systems because: (1) neurochemical and morphologic studies implicate selective involvement of cholinergic systems; and (2) clinical pharmacologic evidence indicates that dystonic CP responds to anticholinergic drugs. The nature of the involvement of striatal cholinergic systems in this model has yet to be elucidated; while biochemical cholinergic markers are transiently decreased following asphyxial injury, the density of cholinergic neurons appears to be increased. This proposal will first examine the effect of asphyxial injury on the number of striatal cholinergic neurons, and their distribution, by immunostaining with a monoclonal antibody to choline acetyltransferase (CAT) and quantitating neurons in serial sections. this analysis will be performed on rats at 3 and 8 weeks of age. The proposal will also study the effect of asphyxia on the distribution of striatal cholinergic fibers. Quantitative assessment of changes in fiber density and distribution will be performed by densitometry and image analysis. These morphologic studies will be correlated with radiochemical assay of CAT activity, measured in subregions of the striatum. These morphologic and biochemical assessments of presynaptic cholinergic components will be correlated with assay of postsynaptic muscarinic cholinergic receptors, differentiated into their subtypes, M1 and M2. These determinations will be made by parallel assay of total muscarinic binding (using 3H-QNB) and M1 binding (using 3H-pirenzepine). Because preliminary studies suggest that cholinergic neurons may be selectively spared in striatal asphyxial injury, this proposal will also determine whether a particular class of small striatal neurons, the GABAergic neurons, are diminished. This will be done by a quantitative analysis of striatal GABA neurons, demonstrated by a monospecific antiserum to GABA. It is expected that the information provided by this proposal will help provide a rational basis for therepeutic approaches to dyskinetic CP.
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