Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6-hydroxydopamine (6-OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6-OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT-PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co-administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation.