Pacemaking in Dopaminergic Ventral Tegmental Area Neurons: Depolarizing Drive from Background and Voltage-Dependent Sodium Conductances
Open accessAbstract
Dopaminergic neurons in the ventral tegmental area (VTA) fire spontaneously in a pacemaker-like manner. We analyzed the ionic currents that drive pacemaking in dopaminergic VTA neurons, studied in mouse brain slices. Pacemaking was not inhibited by blocking hyperpolarization-activated cation current ( I h ) or blocking all calcium current by Mg 2+ replacement of Ca 2+ . Tetrodotoxin (TTX) stopped spontaneous activity and usually resulted in stable resting potentials near −60 mV to −55 mV, 10–15 mV below the action potential threshold. When external sodium was replaced by N -methyl- d -glucamine (NMDG) with TTX present, cells hyperpolarized by an average of −11 mV, suggesting a significant resting sodium conductance not sensitive to TTX. Voltage-clamp experiments using slow (10 mV/s) ramps showed a steady-state, steeply voltage-dependent current blocked by TTX that activates near −60 mV, as well as a sodium “background” current with little voltage sensitivity, revealed by NMDG replacement for sodium with TTX present. We quantified these two components of sodium current during the pacemaking trajectory using action potential clamp. The initial phase of depolarization, up to approximately −55 mV, is driven mainly by non-voltage-dependent sodium background current. Above −55 mV, TTX-sensitive voltage-dependent “persistent” Na current helps drive the final phase of depolarization to the spike threshold. Voltage-dependent calcium current is small at all subthreshold voltages. The pacemaking mechanism in VTA neurons differs from that in substantia nigra pars compacta (SNc) neurons, where subthreshold calcium current plays a dominant role. In addition, we found that non-voltage-dependent background sodium current is much smaller in SNc neurons than VTA neurons.
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Nigral dopaminergic neurons are less abundant with L-type Ca2+ channels, have low oscillations of Ca2+, more expressed calcium-binding proteins calbindins, and therefore exhibit lower susceptibility to damage in PD.
“For example, nigral neurons are less abundant with the L-type Ca2+ channels and are characterized by low oscillations of Ca2+, more expressed calcium-binding proteins calbindins, and therefore exhibit lower susceptibility to damage in PD (Khaliq and Bean 2010).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Khaliq and Bean 2010
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- Authors
- Khaliq, Z. M., & Bean, B. P.
- Affiliations
- Harvard University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-05-26
- Volume
- 30
- Issue
- 21
- Pages
- 7401-7413
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2892804
- OpenAlex
- W2079286959
- Cited by
- 261
- References
- 88
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 18 · 2023: 25 · 2022: 13 · 2021: 24 · 2020: 22 · 2019: 18 · 2018: 10 · 2017: 18 · 2016: 19 · 2015: 14 · 2014: 19 · 2013: 10 · 2012: 13
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS036855, F31NS047991, R37NS036855, NS 36855)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- pacemaking, dopaminergic neurons, ventral tegmental area, spontaneous firing, persistent sodium current, voltage-dependent sodium current, hyperpolarization-activated current, calcium current, substantia nigra pars compacta, action potential threshold, resting membrane potential
- MeSH terms
- Animals, Biological Clocks, Biophysics, Calcium, Dopamine, Electric Stimulation, Glutamates, Membrane Potentials, Mice, Transgenic, Neurons, Tetrodotoxin, Tyrosine 3-Monooxygenase, Valine, Sodium Channels, Ventral Tegmental Area, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, 6-Cyano-7-nitroquinoxaline-2,3-dione, Sodium Channel Blockers, Green Fluorescent Proteins, Mice, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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