N° de poster: P10.05 Globus Pallidus Contribution to Motor Behaviour in Normal and Parkinson's Disease States: Optogenetic Studies in murine models
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The degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease (PD) triggers a range of functional compensatory changes in basal ganglia (BG) circuits that lead to development of motor symptoms. Excessive inhibition of external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to the expression of motor symptoms because of its widespread projections to all BG nuclei and to the thalamus and the cortex. While electrophysiological investigations in animal models of PD provide support for this view, behavioral studies assessing beneficial effects of global GPe stimulations in the context of dopamine (DA) depletion are scare and the reported results are controversial. Here, we used an optogenetic approach and the standard unilateral 6-hydroxydopamine (6-OHDA) nigrostriatal dopamine (DA) lesion model of PD to assess beneficial effects of GPe stimulation on motor deficits in mice. The behavioral effects of optogenetic inhibition of GPe were also studied in normal mice under the same testing conditions to verify whether reduced GPe activity reproduces the typical motor deficits of DA lesion. To modulate GPe activity, the excitatory opsin, ChR2(H134R), and the inhibitory opsin, iC++, were expressed in all neurons under the control of the human synapsin-1 promoter using an adeno-associated virus vector. Global unilateral GPe activation restores a range of motor deficits (ipsilateral circling behavior, forelimb use akinesia, locomotor hypoactivity and bradykinesia) in hemi-parkinsonian mice at optical stimulation parameters ineffective in non-lesioned controls. Unilateral photoinhibition of GPe in normal mice did not impair locomotor behavior indicating that mere reduction of GPe activity is not sufficient for mimicking motor deficits of DA lesion. Bilateral GPe photoinhibition had also no effect on spontaneous locomotor activity but it reduced exploration directed towards sailient spatial cues (illuminated nose-poke modules), suggesting that recruitment of GPe may vary depending on the motor behavior. Collectively, these findings shed a new light on the functional role of GPe and suggest that complex structural and functional compensatory remodeling of GPe efferent neurons may contribute to motor deficits of PD.
