Calcium dynamics control K-ATP channel mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study

Burst firing in medial substantia nigra dopamine (mSN DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium channels (K-ATP) both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is un-known. We show experimentally that L-type calcium channel activity in mSN DA neurons en-hances open probability of K-ATP channels. We then generated a mathematical model to study the role of Ca²⁺ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca²⁺ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, co-application of NMDA and a selective K-ATP channel opener, NN414, are required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca²⁺ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca²⁺ buffering, as might be expected in the calbindin-positive DA SN subpopulation, promote rhyth-mic bursting pattern, consistent with experimental observations in vivo.

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