Contribution of striatal interneurons to L-DOPA induced dyskinesia development in an animal model of Parkinson?s disease.

GOMEZ G; TARAVINI IR; MURER MG; GERSHANIK OS

San Diego, California

Congreso; 19 th International Congress of Parkinson´s Disease and Movement Disorders; 2015

International Parkinson´s Disease and Movement Disorders Society

Objective: To determine changes in number and activity of the different populations of striatal interneurons in a mouse model of hemiParkinsonism and L-DOPA induced dyskinesias. Background: The administration of 3,4-dihydroxyphenyl-l-alanine (L-DOPA) still remains as the preferred treatment for Parkinson?s disease (PD) despite its propensity to induce severe motor complications, known as L-DOPA-induced dyskinesias (LID). Maladaptive changes in the striatum, as well as in other brain areas, are thought to underlie the development of LID. Even though interneurons comprise only 5% of all striatal neurons, they strongly modu- late striatal output. Therefore, changes in striatal microcircuits may contribute to basal ganglia dysfunction in a number of Movement Disorders such as PD and in LID development. Methods: C57 mice were injected with 6-hydroxydopamine (6- OHDA) or vehicle in the medial forebrain bundle and treated daily with a dyskinetogenic dose of L-DOPA or saline solution. LID and reversal of forelimb asymmetry (a measure of anti-Parkinsonian response) were assessed on days 1, 4, 8, 12 and 14. Fixed tissue sections from the striatum and substantia nigra pars compacta were obtained and the severity of the dopaminergic lesion was analyzed by tyrosine hydroxylase immunohistochemistry. The density of each type of interneuron population was determined in the different exper- imental groups by performing immunohistochemical stains for specific interneuron markers. The activity of each interneuron type was assessed by colocalization of each interneuron marker with c-fos.Results: Changes in c-fos and interneuron markers were observed both after dopaminergic depletion and LID development. 6-OHDA lesion led to reduced number of parvalbumin positive interneurons and this change was not reversed by L-DOPA administration. On the other hand, no significant changes were observed in the number of involve prominent loss of cholinergic interneurons within the different experimental groups.Conclusions: Our findings suggest that changes in striatal inter- neurons contribute to the maladaptive state that occur after dopamine depletion. In addition, chronic treatment with L-DOPA fails to reestablish the initial physiological scenario. Further functional studies are required to elucidate if these changes are just an epiphenomenon or if they actually contribute to LID development.