Pacemaking and Bursting in Midbrain Dopamine Neurons

Midbrain dopamine neurons are implicated in many disorders of dopamin signaling, including addiction, schizophrenia and Parkinson’s disease.In vivo, they exhibit two primary activity patterns, tonic (singlespike) firing and phasic bursting The spontaneous tonic firing ofthese neurons plays a fundamental role in dopaminergic signaling by setting the basal level of dopaminergic tone in the striatum andsetting the gain for phasic reward signaling. Visualization of the 3Dstructure of the axon initial segment (AIS) and the somatodendriticdomain of mouse dopaminergic neurons, which were previously recordedin vivo, revealed a positive correlation of the firing rate with bothproximity and size of the AIS. Computational modeling showed that thesize of the AIS is the major causal determinant of the tonic firingrate, by virtue of the higher intrinsic frequency of the isolated AIS,whereas position correlates with firing rate only due to a correlationbetween size and position. Thus morphology plays a critical role insetting the basal tonic firing rate. Transitions from tonic to phasicsignaling (bursting) are modulated by two potassium currents, thesmall conductance (SK) calcium-activated potassium current and theATP-mediated potassium (K-ATP) current, which have opposite effects onbursting. Blocking the SK current de-regularizes firing and increasesbursting, whereas silencing K-ATP channels greatly reduces burstfiring in a medial subpopulation of these neurons. This result seemsparadoxical in light of the putative indirect Ca2+-dependence of theK-ATP channel: why would two calcium-dependent potassium currents have diametrically opposed effects on bursting? In order to address thisquestion, we used a computational model to show that the faster time scale of the SK current prevents plateaus, whereas the presumed slower time scale of the K-ATP current enables the pauses between bursts.