264 | Evaluation of the therapeutic potential D5 receptors ablation in striatal cholinergic interneurons in a mouse model of Parkinson’s disease.

Sensory and Motor Systems

Author: Kianny Miroslava Sanchez Armijos | Email: kianny.sanchez97@gmail.com

Kianny M. Sanchez , Agostina M. Stahl , Andrés Varani , Juan E. Belforte , Jesica Unger , M. Gustavo Murer , Cecilia Tubert

1° Universidad de Buenos Aires – CONICET. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Facultad de Medicina, Departamento de Ciencias Fisiológicas. Grupo de Neurociencia en Sistemas. Buenos Aires, Argentina.

Striatal cholinergic interneurons (SCIN) are the main source of striatal ACh. In Parkinson´s disease (PD), dopaminergic neurons that innervate the striatum degenerate, leading an increase of cholinergic function that contributes to PD symptoms. The gold standard therapy for PD is L-dopa administration, but prolonged treatment may result in dyskinesia.
Recent studies showed that selective modulation of SCINs activity reduces motor deficits have renewed the interest in understanding the mechanisms that alter SCIN function. SCIN become hyperexcitable in parkinsonian and dyskinetic mice due to an increased ligand-independent activity of D5 receptors(D5R). Reducing D5R ligand-independent activity with D1/D5 inverse agonists restores SCIN’s normal physiology. Our aim is to clarify the role of D5R in SCINs activity and evidence the potential therapeutic value of reducing the expression of the D5R in these interneurons. For this, we will use two strategies to remove the D5R in SCIN: ChAT-Cre; D5flox/flox mice, to induce D5R ablation from all cholinergic neurons during development, and, D5flox/flox mice injected with a ChAT-Cre viral vector in the striatum, which would allow a selective ablation from SCIN in adulthood. Both groups will be lesioned with 6-OHDA to induce parkinsonism, and treated with L-dopa to induce dyskinesia. We will perform behavioral evaluations for symptoms of parkinsonism and dyskinesias, electrophysiological validations, and immunohistochemical analyses.