Deletion of NMDA receptors in cholinergic neurons increases L-Dopa induced dyskinesia

JUAN PABLO BECCARIA; LORENA RELA; RODRIGO M PAZ; JUAN BELFORTE; AGOSTINA M STAHL; DIEGO PAFUNDO; MARIO GUSTAVO MURER

Villa Carlos Paz, Cordoba

Congreso; XXXIV reunion anual SAN; 2019

Sociedad Argentina de Investigación en Neurociencias

Parkinson´s disease (PD) is caused by the degeneration of the nigrostriatal dopaminergic projection to the striatum, a key nucleus for the selection of motor programs. L-dopa therapy is the best symptomatic treatment, however, abnormal movements (L-dopa-induced dyskinesia-LID) emerge with disease progression and long term treatment. Striatal cholinergic interneurons are key modulators of striatal circuits, are hyperexcitable in animal models of PD and more excitable in animals with LID. NMDA glutamate receptors (NMDAR) have been linked to LID; in fact the non-competitive NMDAR antagonist amantadine is used as an antidyskinetic agent. Here we used the Cre-loxP system to generate mice with a deletion of the NMDAR1 subunit (NR1) in cells expressing choline acetyltransferase (ChAT.NR1-KO) to ask if NMDAR in cholinergic cells contribute to LID development. Behavioral assessment of ChAT.NR1-KO mice showed no motor impairment compared with control mice. Moreover, the parkinsonian phenotype induced by unilateral nigrostriatal lesion with 6-OHDA was not modified by NR1 deletion. Mice were then treated with increasing doses of L-dopa for three weeks and LID were scored. Unexpectedly, ChAT.NR1-KO mice showed more severe LID compared with control mice, at low doses of L-dopa only, suggesting that NMDAR in cholinergic neurons reduce LID sensitization during repeated L-dopa administration. Overall, the data suggest that NMDAR located on cholinergic neurons have antidyskinetic effects.