Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease

Abstract

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson's disease and Huntington's chorea. With the loss of neurons in the striatum of patients with Huntington's disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of gamma-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

Noninvasive method of immortalized neural stem-like cell transplantation in an experimental model of Huntington's disease

“…Intrastriatial lesions created using excitatory amino acid mimic the neurochemical and neuropathological characteristics of HD (DiFiglia, 1990), and anatomical and functional recovery induced by striatal grafts has been observed (Armstrong et al, 2000;Chen et al, 2002). However, the possibility of acute tissue reaction by quinolinic acid may enabled NSC to migrate into the striatum in the present study.…”

“…To modify disease progression, fetal tissue transplantation in the striatum has been tried in humans (Hauser et al, 2002;Gaura et al, 2004). The transplantation of neural tissue improves functional and morphological outcomes, restores electrophysiological sensitivity to dopamine (Chen et al, 2002), and neuronal differentiation and fiber outgrowth from grafts in an animal model of HD (Armstrong et al, 2000).…”

Stem cell‐based cell therapy for Huntington disease: A review

“…25,32 Transplantation of appropriate cell types enabled new development of afferent and efferent functional connections with correct targets in the host brain. 40 Neural transplantation in HD animal models could modify disease progression, 41,42 improve functional outcome in these animals, 10,11,25,[32][33][34]43 restore electrophysiological sensitivity to dopamine, and induce neuronal differentiation with fiber outgrowth from the grafts. 42 There have been only two studies so far of cell transplantation in transgenic HD mice, while striatal cell transplantation has been performed mostly in excitotoxic lesion models.…”

Neuromodulation of Hippocampal Synaptic Plasticity, Learning, and Memory by Noradrenaline

“…With the loss of neurones in the striatum of patients with HD, there is an associated downregulation of the dopamine receptors, which may modulate the dopamine-mediated responses. Dopamine-mediated electrophysiological potentials have been studied in QUIN-induced experimental disease in rats; QUIN resulted in reduced responses to dopamine in the striatal neurones [102].…”