D-123 | Evaluation of the therapeutic potential of 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^1°, Agostina M. Stahl^1°, Agostina Presta^1°,  M. Gustavo Murer^1°, Cecilia Tubert^1°

^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), the degeneration of dopaminergic neurons innervating the striatum leads to increased cholinergic activity, which contributes to PD symptoms. While L-dopa remains the gold standard therapy, prolonged treatment can result in dyskinesia. Although selective modulation of SCIN activity influences dyskinesia, the underlying mechanisms remain uncertain. SCIN become hyperexcitable in parkinsonian dyskinetic mice due to an increased ligand-independent activity of dopamine D5 receptors (D5R). Reducing this activity with D1/D5 inverse agonists restores SCIN’s normal physiology. Our study aims to clarify the role of SCIN D5R in L-dopa-induced dyskinesia. We explored the therapeutic potential of reducing D5R expression in SCIN by generating ChAT-Cre+/-;D5R/flox+/+ mice lacking D5R expression in cholinergic neurons. Both ChAT-Cre+/-;D5R/flox+/+ and control D5Rflox+/+ mice were lesioned with 6-OHDA to induce parkinsonism and treated with L-dopa to induce dyskinesia. Preliminary data show a decrease in dyskinesia in D5R ablated mice. We plan to extend this research by selectively eliminating D5R from striatal neurons in adult mice with an AAV vector-approach.