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

Abstract

Burst firing in medial substantia nigra (mSN) dopamine (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 (K-ATP) channels both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is unknown. We show experimentally that L-type calcium channel activity in mSN DA neurons enhances open probability of K-ATP channels. We then generate a mathematical model to study the role of Ca dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca 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, coapplication of NMDA and a selective K-ATP channel opener, NN414, is required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca 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 Ca buffering, as might be expected in the calbindin-positive SN DA neuron subpopulation, promote rhythmic bursting pattern, consistent with experimental observations in vivo. NEW & NOTEWORTHY Recently identified distinct subpopulations of midbrain dopamine neurons exhibit differences in their two primary activity patterns in vivo: tonic (single spike) firing and phasic bursting. This study elucidates the biophysical basis of bursts specific to dopamine neurons in the medial substantia nigra, enabled by ATP-sensitive K channels and necessary for novelty-induced exploration. A better understanding of how dopaminergic signaling differs between subpopulations may lead to therapeutic strategies selectively targeted to specific subpopulations.

α-Endosulfine regulates amyloid β 42 via the modulation of neprilysin activity

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Subthreshold repertoire and threshold dynamics of midbrain dopamine neuron firingin vivo

“…These results indicate that our patch pipette solution sufficiently approximated an unperturbed intracellular in vivo milieu of individual midbrain dopamine neurons regarding buffering (e.g. calcium) as well as energy and redox metabolism, which are tightly coupled to excitability (Knowlton et al, 2018;Schiemann et al, 2012;Subramaniam et al, 2014). In addition, once the standard whole-cell configuration was established, electrical discharge properties remained stable for at least a few minutes ( Fig.…”

Sensory neuropathy and nociception in rodent models of Parkinson's disease

“…The selective vulnerability of DA neurons of the substantia nigra pars compacta (SNpc; Box 1) has been the focus of research (Burbulla et al, 2017; Guzman et al, 2010; Liss et al, 2005) leading to the concept that autonomous pacemaking (Box 1) in these neurons leads to sustained calcium influx through L-type calcium channels (Surmeier et al, 2011). Cytosolic calcium overload causes mitochondrial oxidative stress (Dryanovski et al, 2013) and subsequent redox modification of ATP-sensitive potassium channels (K-ATP) (Knowlton et al, 2018) that control the spontaneous tonic pacemaker activity (Liss et al, 2001, 2005; Schiemann et al, 2012), which may lead into a vicious cycle. Although nociceptive neurons are not spontaneously active, L-, N- and T-type voltage-gated calcium channels and K-ATP essentially contribute to the enhancement (calcium channels) (Alles et al, 2018; Candelas et al, 2019; Choi et al, 2016; Neugebauer et al, 1996) or lowering (K-ATP) of nociceptive neuron excitability (Kawano et al, 2009; Rodrigues and Duarte, 2000).…”