Phasic activation of midbrain dopamine neurons is critical for flexible switching of behavioural strategies in response to salient environmental cues. We discovered a novel, cell-type-specific function of ATP-sensitive potassium channels (KATP) in promoting a switch from tonic to phasic (burst) firing of dopamine neurons in vivo. Thus, functional KATP channels are necessary for burst discharges in a subpopulation of dopamine neurons of the medial substantia nigra (SN) in mice, as well as their exploratory behaviour in response to spatial novelty. Moreover, in vitro studies demonstrated that opening of KATP channels facilitated NMDA receptor-mediated excitability in medial SN dopamine neurons. As important metabolic sensors, KATP channels can fine tune phasic firing, thence acting as a 'gateway' between energy metabolism and motor action control.

Using post-mortem tissue, we detected selective up-regulation of transcripts for KATP channel and NMDAR1 receptor subunits in Parkinson disease (PD) patients compared to control subjects, linking KATP channels to pathogenesis in PD. Furthermore, electrophysiological recordings of surviving dopamine neurons in PD patients showed high levels of burst firing in line with enhanced KATP channel and NMDA receptor expression. By boosting striatal dopamine release, increased burst firing in SN dopamine neurons might play a homeostatic role in PD. However this might also be maladaptive in leading to chronic excitotoxicity and contributing to the neurodegenerative process itself. Indeed, we previously demonstrated a protective role of KATP gene inactivation in mouse models of PD (Liss et al. 2005, Nature Neurosci), supporting the notion of a toxic gain-of-function for KATP channels in the degeneration of dopamine midbrain neurons.