DOPA Yanıtlı Distoni Fare Modelinde Striatal Kolinerjik Sistemin Rolü

Abstract

Dystonia, which is the third most common movement disorder, is a heterogeneous group of diseases both etiologically and pathophysiologically. Striatal cholinergic dysfunction is a common pathophysiologiccal mechanism associated with various forms of both genetic and secondary dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this thesis, a recently developed knock-in mouse model homozygous for the c.1160C>A TH mutation, which is homologous to human dopamine responsive dystonia (DRD) causing TH mutation p.381Q>K, with strong symptomatic responses to L-DOPA and anti-cholinergic drugs was used, to assess the changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs). Unbiased stereological neuronal counts were used for detecting possible changes in the number of striatal ChIs and to determine the potential effect of aging on the number of ChIs in both young (3 months old) and aged (15 months old) mice. No significant difference was found in the total number of ChAT-positive neurons in any of the functional striatal regions examined, except in the dorsal division of the post-commissural striatum where a significantly larger number of ChAT-positive neurons was counted in DRD mice compared to controls (p < 0.05). No change in the number and distribution of ChIs was found in aged animals. Subtle but statistically significant decrease in the extent and complexity of the dendritic tree of ChIs were found in middle and caudal regions of the striatum in DRD mice compared to controls (p < 0.05). Additional immunohistochemical data also suggested lack of significant change in the expression of striatal cholinergic M1 and M4 muscarinic receptors immunoreactivity in DRD mice. As changes in GABAergic parvalbumin (PV)-immunoreactive striatal interneurons were also accused in the pathophysiology of dystonia, the number of PV-positive neurons was also evaluated in only young mice, showing no change between DRD and control mice. Tyrosine hydroxylase (TH) immunostaining revealed increase in the number of TH-positive cells throughout the striatum more prominent in the rostral, middle and ventral regions in DRD mice only. Electon microscopic imaging of dopaminergic and cholinergic terminals in the striatum did not show any significant change. In conclusion, the decrease in the extent and complexity of the dendritic tree of striatal ChIs in the DRD mouse model may be an important antecedent finding that may shed light on the pathophysiology of dystonia, and this finding should be investigated with further methods.