Characterization of striatal TH-immunoreactive cells in chronic and acute L-DOPA treatment in a mice model of Parkinson?s disease

GOMEZ G; BORDONE M; SANZ BLASCO S; BERNARDI MA; FERRARIO JE; TARAVINI IR; MURER MG; GERSHANIK OS

Berlín

Congreso; 20th International Congress of Parkinson´s Disease and Movement Disorders; 2016

International Parkinson´s Disease and Movement Disorders Society

Objective: To characterize Tyrosine Hydroxylase immunoreactive cells (TH-ir) in a mouse model of hemi parkinsonism and L-DOPA induced dyskinesia.Background: L-DOPA-induced dyskinesias (LID) are a severe motor complication occurring frequently in Parkinson?s disease (PD) patients treated chronically with L-DOPA (3,4-dihydroxyphenyl-l-alanine). Striatal TH expressing cells have been described in some PD patients and animal models of PD and LID. Their presence in control animals and whether they represent a shift in phenotype expression is still controversial. Furthermore, their ability to synthesize dopamine (DA) and their implication in LID remains inconclusive.Methods: C57 mice were injected with 6-hydroxydopamine (6-OHDA) or vehicle in the medial forebrain bundle and treated daily with L-DOPA or saline. In addition, a subset of 6-OHDA injected-saline treated mice received an acute dose of L-DOPA. LID and reversal of forelimb asymmetry were assessed during treatment. Dopaminergic lesion and the presence of striatal TH-ir cells were analyzed by TH immunohistochemistry. Co-localization with c-fos was evaluated to determine cell activity. Co-immunofluorecent stains of TH and interneuronal markers were performed. We conducted the same LID protocol using a transgenic mice line expressing fluorescent green or red fluorescent proteins in Medium Spiny Neurons (MSN) that express D2 or D1 receptor respectively, and we analyzed their co-localization with TH expressing cells.Results: Striatal TH-ir cells were not present in control animals or in DA depleted-vehicle treated mice. Lesioned mice treated with vehicle who received an acute dose of L-DOPA did not show TH-ir cells either. However, they did appear in dyskinetic mice receiving a chronic treatment with L-DOPA and with LID development, and all of them expressed c-fos. TH-ir cells did not co-localize with any of the interneuronal markers studied.Conclusions: Our findings suggest that striatal TH-ir cells are only present in dyskinetic animals receiving a chronic, but not an acute dose of L-DOPA. Furthermore, we showed that these cells do not express interneuron markers and might be a subset of MSN that express TH after LID development in DA depleted animals. Further functional studies are required to elucidate if these neurons produce DA and their role after DA denervation and pharmacological DA replacement.