CHANGES IN NEURAL CONNECTIVITY BTW PARVALBUMIN-EXPRESSING INTERNEURONS & MEDIUM SPINY NEURONS IN HEMIPARKINSONIAN AND L-DOPA-INDUCED DYKINETIC MICE

J BELFORTE; IRE TARAVINI; MG MURER; G GOMEZ; OS GERSHANIK

Workshop; ISN-JNC Flagship School Construction and reconstruction of brain circuits: Normal and pathological axon guidance; 2018

L-dopa-induced dyskinesia (LID) remains as the major problem in the treatment of Parkinson?s disease.Striatal Fast Spiking interneurons, expressing the calcium binding protein parvalbumin, are the major componentof a feed-forward inhibition mechanism that regulates striatal network function by affecting spike timing inmedium spiny neurons (MSNs) and, therefore, they could be involved in the abnormal firing pattern of MSNsproposed to underlie LID development. Using bacterial artificial chromosome double transgenic mice expressingtdTomato in D1 receptor-MSNs and enhanced green fluorescent protein in D2 receptor-MSNs, we have studiedchanges in PV-positive interneuron connectivity onto MSNs of both the D1R and D2R pathways, in anexperimental model of hemiparkinsonism (mouse injected with 6-hydroxydopamine in the medial forebrainbundle), both in the parkinsonian and dyskinetic condition induced by chronic L-DOPA treatment. By immunohistochemistryand confocal microscopy, we determined changes in perisomatic GABAergic boutons densityonto MSNs by measuring the number of contacts originated from parvalbumin containing striatal interneurons,in both cell types as well as the number of vesicular GABA transporter contacts. We also explored thedifferential expression of striatal activity-regulated cytoskeleton-associated protein (Arc) and c-Fos in both typesof MSNs as a measure of neuronal activation. Our results show differential modifications in perisomaticGABAergic connectivity and neuronal activation in MSN populations suggesting an attempt by the system toregain homeostasis after denervation and an imbalance between excitation and activation of both types of MSNsleading to the development of dyskinesia after exposure to L-DOPA.