Recovery of the fullin vivofiring range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

Abstract

Substantia nigra dopamine (SN DA) neurons are progressively lost in Parkinson disease (PD). While the molecular and cellular mechanisms of their differential vulnerability and degeneration have been extensively studied, we still know very little about potential functional adaptations of those SN DA neurons that at least for some time manage to survive during earlier stages of PD. We utilized a partial lesion 6-OHDA mouse model to characterize initial electrophysiological impairments and chronic adaptations of surviving identified SN DA neurons, both in vivo and in vitro. Early after lesion (3 weeks), we detected a selective loss of in vivo burst firing in surviving SN DA neurons, which was accompanied by in vitro pacemaker instability. In contrast, late after lesion (>2 months), in vivo firing properties of surviving SN DA neurons had recovered in the presence of 2-fold accelerated pacemaking in vitro. Finally, we show that this chronic cell-autonomous adaptation in surviving SN DA neurons was mediated by Kv4.3 channel downregulation. Our study demonstrates substantial homeostatic plasticity of surviving SN DA neurons after a single-hit non-progressive lesion, which might contribute to the phenotype of initially surviving SN DA neurons in PD.

Dendritic involvement in inhibition and disinhibition of vulnerable dopaminergic neurons in healthy and pathological conditions

“…Therefore, striatal disinhibition of the dopaminergic neurons through the SNr could be enhanced under dopamine-depletion conditions. Together, the disrupted inhibition pathway and the potentially-enhanced disinhibition pathway could play a role in the progression of PD pathology, resulting in hyper-excitability of the remaining dopaminergic neurons ( Kovacheva et al, 2021 ) and potentially increasing their susceptibility to neurodegeneration.…”