Dyskinesia induced by optogenetic stimulation of striatonigral axon terminals in naive and L- DOPA primed parkinsonian mice

PAFUNDO, DIEGO ESTEBAN; RUIZ?DEDIEGO, IRENE; MORATALLA, ROSARIO; KEIFMAN, ETTEL; MURER, MARIO GUSTAVO

Berlin

Congreso; 11th FENS Forum of Neuroscience; 2018

FENS (Federación Europea de Sociedades de Neurociencia)

L-DOPA-induced dyskinesia (LID) remains as a major complication of chronic L-DOPA therapy in Parkinson´s disease. LID emerges as a result of the pulsatile dopaminergic stimulation provided by high doses of L-DOPA and the degree of dopamine (DA) denervation. Here we asked if, by optogeneticaly stimulating the densely packed direct medium spiny neurons (dMSN) terminals at the substantia nigra reticulata (SNr) rather than the broadly distributed dMSN cell bodies at the striatum, we could induce a greater inhibition of SNr and therefore recruit more intense and varied dyskinetic movements than those shown in previous studies. We also analyzed the priming effect of escalating L-DOPA doses on these abnormal involuntary movements (AIMs). Adult C57 sham or dopamine depleted by 6-hydroxydopamine injection in MFB mice were used. Channelrhodopsin expression was achieved by an adeno-associated virus injected into the striatum. Optic fibers were implanted over SNr or external globus pallidus. Overall, our data show that optostimulation of dMSN terminals induces a wide repertoire of AIMs (optostimulation-induced dyskinesia; OID) in 6-hydroxydopamine animals naive to pharmacological treatment. Also, OID scores were consistently higher in animals primed with L-DOPA when compared to naive. Compared to LID scores caused by moderate or even high doses of L-DOPA, OID scores were higher. Also, OID could not be increased further by applying simultaneously optostimulation with moderate or high doses of L-DOPA. In conclusion, our findings suggest that striatonigral inhibition of basal ganglia output may be a decisive mechanism mediating LID.