Ca<sub>v</sub>1.3 Channel Voltage Dependence, Not Ca<sup>2+</sup>Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons

Putzier, Ilva; Kullmann, Paul H. M.; Horn, John P.; Levitan, Edwin S.

doi:10.1523/jneurosci.4742-09.2009

Cited by 135 publications

(151 citation statements)

References 30 publications

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“…The subthreshold Ca 2+ -K + oscillatory mechanism underlies the generation of low frequency background firing in a significant subpopulation of DA neurons [7][8][9][10][11][12][13][14][15][16][17][18]51]. However, a number of studies suggest a contribution of Ca 2+ -independent currents to oscillations [26,19,25,27,46]. In accord with these studies, we found that, if considered in isolation, the Ca 2+ -K + oscillatory mechanism provides type II excitability, which is incompatible with the experiments reproduced above.…”

Section: Influence Of Intrinsic Currents On the Type Of Excitabilitysupporting

confidence: 73%

Dopamine neurons change the type of excitability in response to stimuli

Morozova

Zakharov²,

Gutkin

et al. 2016

Preprint

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The dynamics of neuronal excitability determine the neuron's response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency "balanced" state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or coactivation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I excitability in dopamine neurons might be important for low firing rates and fine-tuning basal dopamine levels, while switching excitability to type II during NMDAR and AMPAR activation may facilitate a transient increase in dopamine concentration, as type II neurons are more amenable to synchronization by mutual excitation. Author SummaryDopamine neurons play a central role in guiding motivated behaviors. However, complete understanding of computations these neurons perform to encode rewarding and salient stimuli is still forthcoming. Network connectivity influences neural responses to stimuli, but so do intrinsic excitability properties of individual neurons, as such properties define synchronization qualities and neural coding strategy. We investigated the excitability type of the DA neuron and found that, depending on the synaptic and intrinsic current composition, DA neurons can switch from type I to type II excitability. In short, without synaptic inputs or under balanced excitatory and inhibitory inputs DA neurons exhibits type I excitability, w...

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Section: Influence Of Intrinsic Currents On the Type Of Excitabilitysupporting

confidence: 73%

Dopamine neurons change the type of excitability in response to stimuli

Morozova

Zakharov²,

Gutkin

et al. 2016

Preprint

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“…First, we observed extremely high expression levels of the big potassium (BK) channel (encoded by the potassium large conductance calcium-activated channel gene; Kcnma1) and the Cacnb3 (voltage-gated calcium channel auxiliary b3 subunit). In addition, the L-type voltage-gated calcium channel a1d (Cacna1d, also known as Cav1.3), although not present in the microarray, is highly expressed in these neurons (see Allen Brain Atlas: http://mouse.brain-map.org/experiment/show/68798037) and has been shown to drive pacemaker activity in dopamine (DA) neurons (22). We were also interested in the pacemaking HCN channels, which are differentially expressed in the habenula (16,23).…”

Section: Trap Analysis Of Cholinergic Mhb Neurons Reveals Enrichment Ofmentioning

confidence: 99%

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Görlich

Antolin-Fontes

Ables

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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The discovery of genetic variants in the cholinergic receptor nicotinic CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula-interpeduncular axis as a critical relay circuit in the control of nicotine dependence. Although clear roles for α3, β4, and α5 receptors in nicotine aversion and withdrawal have been established, the cellular and molecular mechanisms that participate in signaling nicotine use and contribute to relapse have not been identified. Here, using translating ribosome affinity purification (TRAP) profiling, electrophysiology, and behavior, we demonstrate that cholinergic neurons, but not peptidergic neurons, of the medial habenula (MHb) display spontaneous tonic firing of 2-10 Hz generated by hyperpolarization-activated cyclic nucleotidegated (HCN) pacemaker channels and that infusion of the HCN pacemaker antagonist ZD7288 in the habenula precipitates somatic and affective signs of withdrawal. Further, we show that a strong, α3β4-dependent increase in firing frequency is observed in these pacemaker neurons upon acute exposure to nicotine. No change in the basal or nicotine-induced firing was observed in cholinergic MHb neurons from mice chronically treated with nicotine. We observe, however, that, during withdrawal, reexposure to nicotine doubles the frequency of pacemaking activity in these neurons. These findings demonstrate that the pacemaking mechanism of cholinergic MHb neurons controls withdrawal, suggesting that the heightened nicotine sensitivity of these neurons during withdrawal may contribute to smoking relapse.nAChRs | TRAP profiling T he tobacco epidemic kills nearly six million smokers a year, primarily from lung cancer. The success rate for smoking cessation without pharmacological treatment is only 3-5% and less than 30% with nicotine-replacement therapies (1). Nicotine, the addictive component of tobacco, mediates its action by activating nicotinic acetylcholine receptors (nAChRs), which respond to the endogenous neurotransmitter acetylcholine (ACh). Like other drugs of abuse, chronic nicotine exposure promotes adaptations in neuronal circuits that sustain the use of cigarettes (2, 3). Upon nicotine cessation in humans, a withdrawal syndrome-characterized by negative somatic and affective symptoms such as irritability, anxiety, depressed mood, and loss of concentration-develops (2, 3) and contributes to the high probability of smoking relapse. In rodents that have been chronically treated with nicotine, withdrawal can be induced either by pharmacological precipitation or by cessation of nicotine administration. Somatic and affective signs of withdrawal differentially manifest in these two cases (3, 4). Additionally, studies in knockout mice have revealed a distinct contribution of various nAChR subtypes to somatic and affective withdrawal signs (5, 6), illustrating the molecular complexity of nicotine dependence, withdrawal, and relapse.Converging evidence from genome-wide association studies...

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“…Our contention that Cav1.3 channels are not necessary for pacemaking has been challenged in a recent article (97). The crux of their argument is that they can experimentally restart pacemaking that has been halted with high concentrations of DHP by using dynamic current clamp to reintroduce Cav1.3 channels into the soma.…”

Section: Surmeier Et Almentioning

confidence: 99%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

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Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

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Ca_v1.3 Channel Voltage Dependence, Not Ca²⁺Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons

Cited by 135 publications

References 30 publications

Dopamine neurons change the type of excitability in response to stimuli

Dopamine neurons change the type of excitability in response to stimuli

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

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Cav1.3 Channel Voltage Dependence, Not Ca2+Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons

Cited by 135 publications

References 30 publications

Dopamine neurons change the type of excitability in response to stimuli

Dopamine neurons change the type of excitability in response to stimuli

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Contact Info

Product

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Ca_v1.3 Channel Voltage Dependence, Not Ca²⁺Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons