Recent experiments in animal models of neurodegenerative disorders have demonstrated the exciting possibility of using fetal tissue transplants to reverse the deficits induced by the neurodegenerative process. However, little work has been done to determine how transplanted tissue may replace complex brain degeneration involving multiple neuronal types. Huntington's disease (HD) which is characterized by gross degeneration of a heterogeneous population of intrinsic neurons of the striatum may be an ideal disorder to study the ability of brain tissue transplants to possibly restore function of a major brain area. The excitotoxin kainic acid (KA) provides a useful model of Huntington's disease. It has been demonstrated that transplants of fetal striatum into the KA lesioned rat striatum survives, grows and reverses the spontaneous nocturnal locomotor hyperactivity which is characteristic of the lesion, thereby demonstrating that the transplants are functional in nature. However, relatively little is known about the abilities of transplants to ameliorate the pharmacological deficits induced by excitotoxin lesions. Particular emphasis will be placed on the functional recovery of dopaminergic neurotransmission produced by transplants. The functional pharmacology will be investigated in rats with unilateral striatal KA lesions by assessing rotation behavior in response to apomorphine and D-amphetamine. Rotation behavior will provide a relatively simple quantitative model of asymmetry in dopamine effector systems. We have previously demonstrated that striatal transplants produced a decrease in rotation behavior indicative of the reinstatement of normal pharmacological characteristics in the lesioned striatum. However, autoradiographic analyses on these same rats demonstrated that although the transplant survived and grew within the lesioned striatum it did not express D1 or D2 dopamine receptors. It is proposed that the transplanted material induces changes in the sensitivity of the remaining host tissue to apomorphine. Experiments using transplants of adult adrenal medulla and fetal tissues other than striatum will determine whether the amelioration of pharmacological deficits is specific to striatal tissue. We hypothesize that cells other than neurons in the fetal tissue transplants are responsible for the functional recovery. Astrocytes are the most likely candidates as these glia are known to provide trophic factors necessary for neuronal plasticity. We will investigate the presence of astrocytes in the transplant and host brain using the markers for glial fibrillary acidic protein and vimentin which label mature and immature astrocytes respectively. We will culture astrocytes from various brain regions, transplant these cells into lesioned striatum and determine whether recovery of pharmacological deficits are produced. These experiments should help clarify the mechanisms of action and pharmacological characteristics of striatal tissue transplants in a model of HD and should provide information which will be useful in determining the most efficacious procedure for possible use in humans with HD.
