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Synaptic Activity Unmasks Dopamine D2 Receptor Modulation of a Specific Class of Layer V Pyramidal Neurons in Prefrontal Cortex
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Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. In addition to NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca 2+channels and was blocked by the selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca 2+(and Ca 2+-dependent) currents, we measured whole-cell Ca 2+potentials that occur after blocking Na+and K+channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca 2+-channel-dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward-related persistent firing, or increase the level of noise in prefrontal circuits.
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“We found that the D2 receptor is expressed by at least a subset of hiPS cell–derived cortical neurons, similar to what has been reported in vivo49,50”
From Neuronal defects in a human cellular model of 22q11.2 deletion syndrome (2020) · cites this paper as [49]
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“This Gαi coupled receptor has been shown to modulate the function of LTCC48,49.”
From Neuronal defects in a human cellular model of 22q11.2 deletion syndrome (2020) · cites this paper as [49]
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Pathak, A., Brincat, S. L., Organtzidis, H., Strey, H. H., Senneff, S., Antzoulatos, E. G., Mujica-Parodi, L. R., Miller, E. K., & Granger, R. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.06.565902 · Cited by 1
Baker, A. L., & Gulledge, A. T. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.04.652144 · Cited by 1
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A Simple Probabilistic and Point-process Response Model for Predicting Every Spike in OptogeneticsPreprint
Luo, X., Gee, S. M., Sohal, V. S., & Small, D. S. (2012)
Self-citationJoshi, A. (2016) · D-Scholarship@Pitt (University of Pittsburgh)
Storage of spatiotemporal input sequences in dendrites of pyramidal neurons
Macak, M. (2016) · UCL Discovery (University College London)
Hare, B. D., Liu, R. J., Shinohara, R., Pothula, S., Dileone, R., & Duman, R. S. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3155673
Jackson, J. M. (2017) · Scholarship & Creative Works - Digital UNC a service of University Libraries (University of Northern Colorado)
Metadata
- Authors
- Gee, S., Ellwood, I., Patel, T., Luongo, F., Deisseroth, K., & Sohal, V. S.
- Affiliations
- University of California, San Francisco (US)
- Stanford University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-04-04
- Volume
- 32
- Issue
- 14
- Pages
- 4959-4971
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3352768
- OpenAlex
- W1971825082
- Cited by
- 214
- References
- 89
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 16 · 2022: 17 · 2021: 17 · 2020: 15 · 2019: 20 · 2018: 25 · 2017: 17 · 2016: 12 · 2015: 15 · 2014: 15 · 2013: 14 · 2012: 6
- FWCI
- 6.59
- 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
- Howard Hughes Medical Institute
- Simons Foundation
- International Mental Health Research Organization
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (R00MH085946)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- dopamine D2 receptor, prefrontal cortex, layer 5 pyramidal neurons, afterdepolarizations, NMDA receptor, L-type calcium channels, nimodipine, quinpirole, sulpiride, synaptic input, hyperpolarization-activated current, subcortical projections, schizophrenia, persistent firing
- MeSH terms
- Animals, Female, Male, Mice, Inbred C57BL, Neurons, Cell Polarity, Prefrontal Cortex, Receptors, Dopamine D2, Pyramidal Cells, Mice, Synaptic Potentials
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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