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bioRxiv · 10.1101/2020.04.08.032359

M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's Disease

Fernandez-Garcia, S.·Conde-Berriozabal, S.·Garcia-Garcia, E.·Gort-Paniello, C.·Bernal-Casas, D.·Garcia-Diaz Barriga, G.·Lopez-Gil, J.·Munoz-Moreno, E.·Soria, G.·Campa, L.·Artigas, F.·Rodriguez, M. J.·Alberch, J.·Masana, M.
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Abstract

Huntingtons disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of basal ganglia. The cortex is the main striatal afference and progressive cortico-striatal disconnection characterizes HD. We mapped cortico-striatal dysfunction in HD mice to ultimately modulate the activity of selected cortico-striatal circuits to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo suggested prominent functional network deficits in fronto-striatal compared to motor-striatal pathways, which were accompanied by reduced glutamate levels in the striatum of HD mice. Moreover, optogenetically-stimulated glutamate release from fronto-striatal terminals was reduced in HD mice and electrophysiological responses in striatal neurons were blunted. Remarkably, repeated M2 Cortex-dorsolateral striatum optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that the selective stimulation of fronto-striatal pathways can become an effective therapeutic strategy in HD.

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Fernandez-Garcia, S., Conde-Berriozabal, S., Garcia-Garcia, E., Gort-Paniello, C., Bernal-Casas, D., Garcia-Diaz Barriga, G., Lopez-Gil, J., Munoz-Moreno, E., Soria, G., Campa, L., Artigas, F., Rodriguez, M. J., Alberch, J., Masana, M.. 2020-04-10. M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's Disease. https://doi.org/10.1101/2020.04.08.032359

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