Firing pattern modulation through SK channel current increase underlies neuronal survival in an organotypic slice model of Parkinson's disease.

Abstract

Dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) are vulnerable to excitotoxicity in Parkinson's disease (PD). Neurotoxic stimuli may alter the firing patterns of DA neurons. However, whether firing pattern change underlies neurotoxic stress-induced death of DA neurons remains unknown. In this study, we established long-term cultures of SNc organotypic slices and used this model to evaluate the neurotoxic effects on firing mode and DA neuronal viability following chronic treatment with neurotoxin 6-hydroxydopamine (6-OHDA). Using whole-cell patch clamp to explore the intrinsic membrane properties and firing mode, we showed that chronic exposure to 6-OHDA raised the resting membrane potential of SNc DA neurons and altered their firing pattern, causing it to switch from a regular rhythmic pacemaking firing to an irregular bursting. This firing pattern change correlated with increased death of SNc DA neurons. The 6-OHDA-induced firing pattern change correlated with an increase in the activity of the small conductance calcium-activated potassium channel (SK channel) and with an increase in both the level and activity of protein phosphatase 2A (PP2A). Activation of the SK channel by its agonist 1-EBIO attenuated 6-OHDA-induced firing irregularity and death, while the SK channel antagonist apamin exacerbated the toxic effects of 6-OHDA. Thus, SK channel current is a substantial element in sustaining the SNc DA neuronal rhythmic pacemaking and homeostasis and perturbing SK channel activity underlies 6-OHDA-induced neurotoxicity.