Objective: To validate that enhancing potassium-chloride cotransporter activity would restore inhibition and normal function in parkinsonian Substantia nigra reticulata (SNr) and participate to Parkinson’s disease (PD) symptom alleviation.

Background: The SNr is an output nucleus of the basal ganglia with spontaneously active GABA neurons providing inhibition of brain stem and thalamic motor centers involved in basal ganglia-mediated control of locomotion. Disrupted firing of SNr cells is associated with normal movement initiation and in the pathophysiology of PD.

Method: To understand how synaptic changes in the SNr microcircuitry contribute to motor symptoms in PD, we have performed (i) electrophysiological studies on brain slices from mice with parkinsonism induced by 6-OHDA and (ii) behavioural pharmacology investigations in the MPTP-treated macaque.

Results: Optogenetic activation of GABAergic synaptic inputs from the striatum caused a reliable inhibition of SNr in DA-intact mice. In contrast, SNr cells recorded in slices from DA-depleted mice were significantly less sensitive to striatonigral inhibition. The reduction of inhibition in DA-depleted animals was not accompanied by a change in the amplitude of spontaneous inhibitory currents, confirming functional levels of GABAA-receptor expression in DA-depleted animals.

Immunohistological analysis of midbrain tissue from DA-depleted mice and macaque monkeys revealed a significant reduction of the potassium and chloride symporter, KCC2, in the membrane of SNr neurons. Striatonigral activation was ineffective in slices of DA intact mice in the presence of the KCC2 inhibitor VU0463271, confirming that KCC2 is essential for synaptic inhibition in SNr cells. In DA-intact mice, both VU-sensitive outward and VU-insensitive inward spontaneous currents were present when SNr cells were clamped at membrane potentials close to the equilibrium potential for chloride. In contrast, SNr cells in DA-depleted mice had primarily inward currents because of the loss of KCC2 function. This observation prompted us to test the activation of KCC2 in a PD macaque model. While KCC2 activation had no effect on L-DOPA-induced dyskinesia, it had a significant effect on on-time and general activity, extending, although not potentiating, the efficacy of L-DOPA.

Conclusion: We report a new ionic mechanism potentially responsible for aberrant neuronal activity in the basal ganglia output of the Parkinsonian brain.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ionic-plasticity-of-midbrain-gabaergic-synapses-in-pd-models/