A concerted action of L- and T-type Ca2+ channels regulates locus coeruleus pacemaking

Matschke, Lina A.; Bertoune, Mirjam; Roeper, Jochen; Snutch, Terrance P.; Oertel, Wolfgang H.; Rinné, Susanne; Decher, Niels

doi:10.1016/j.mcn.2015.08.012

Cited by 28 publications

(26 citation statements)

References 57 publications

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“…These findings are consistent with data from the thalamus (Dreyfus et al, 2010) and locus ceruleus (Matschke et al, 2015) reporting observations of a T-type "window current," which is a small, subthreshold current thought to result from overlap of activation and inactivation curves. In locus ceruleus neurons, T-type window currents in conjunction with current from L-type Ca 2ϩ channels have been shown to contribute to the robustness of pacemaking (Matschke et al, 2015). Although our experiments in SNc dopamine neurons do not directly test the role of T-type currents in pacemaking, two existing studies show clear effects of pharmacological block of T-type channels on spontaneous firing in SNc neurons.…”

Section: Functional Role For T-type Ca 2؉ Channels In Calb؊ Snc Neuronssupporting

confidence: 91%

Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels

2017

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While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition.

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Section: Functional Role For T-type Ca 2؉ Channels In Calb؊ Snc Neuronssupporting

confidence: 91%

Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels

2017

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“…PD is associated with cell loss in not only the SNpc, but also the locus coeruleus and hypothalamic tuberomammillary nucleus [68]. Intriguingly, these other two regions also exhibit autonomous pacemaking activity, again mediated by Ca v 1.3 [69,70]. These observations reveal a potential correlation between the use of extracellular Ca 2+ for pacemaking and elevated sensitivity both in PD and in MPTP models.…”

Section: Intracellular Ca 2+ and Its Influence On Energy Expenditurementioning

confidence: 88%

Tipping Points and Endogenous Determinants of Nigrostriatal Degeneration by MPTP

Schildknecht

Monte

Pape

et al. 2017

Trends in Pharmacological Sciences

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The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a Parkinson's disease (PD)-like syndrome by inducing degeneration of nigrostriatal dopaminergic neurons. Studies of the MPTP model have revealed the pathomechanisms underlying dopaminergic neurodegeneration and facilitated the development of drug treatments for PD. In this review, we provide an update on MPTP bioactivation and biodistribution, reconcile the distinct views on energetic failure versus reactive oxygen species (ROS) formation as main drivers of MPTP-induced neurodegeneration, and describe recently identified intrinsic features of the nigrostriatal system that make it particularly vulnerable to MPTP. We discuss these new perspectives on the endogenous tipping points of tissue homeostasis and the drivers responsible for vicious cycles in relation to their relevance for the development of novel intervention strategies for PD.

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“…It has been shown that inhibition of the proteasome induced elevation of intracellular Ca 2+ and cell death 70 . As Ca 2+ influx can predispose to oxidative stress and the LC neurons express two Ca 2+ -type channels, it has been suggested that they are particularly vulnerable to Ca 2+ -triggered neurodegeneration in PD 71 with less ability to recover. Interestingly, Matsui et al .…”

Section: Discussionmentioning

confidence: 99%

Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs

Lillethorup

Glud

Alstrup

et al. 2018

Sci Rep

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Impairment of the ubiquitin proteasome system has been implicated in Parkinson’s disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacystin, respectively. Main radioligands included [11C]-DTBZ (vesicular monoamine transporter type 2) and [11C]-yohimbine (α2-adrenoceptor). [11C]-DASB (serotonin transporter) and [11C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [11C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [11C]-yohimbine volume of distribution increased by 18–25% in the pons, grey matter and the thalamus after 200 μg, which persisted at 400 μg (n = 6). In the later subset of minipigs, we observed decreased [11C]-DASB (n = 5) and increased [11C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson’s disease.

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A concerted action of L- and T-type Ca2+ channels regulates locus coeruleus pacemaking

Cited by 28 publications

References 57 publications

Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels

Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels

Tipping Points and Endogenous Determinants of Nigrostriatal Degeneration by MPTP

Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs

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