期刊
JOURNAL OF NEUROSCIENCE
卷 32, 期 14, 页码 4959-4971出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5835-11.2012
关键词
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资金
- Stanford University
- Howard Hughes Medical Institute
- California Institute for Regenerative Medicine
- National Science Foundation
- National Institute of Mental Health (NIMH)
- National Institute on Drug Abuse
- McKnight Foundation
- Coulter Foundation
- Kinetics Foundation
- Keck Foundation
- Staglin Family and International Mental Health Research Organization from NIMH [R00 MH085946-02]
- Simons Foundation for Autism Research
- National Alliance for Research on Schizophrenia and Depression
- Sloan Research Fellowship
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 Ca2+ channels and was blocked by the selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca2+ (and Ca2+-dependent) currents, we measured whole-cell Ca2+ 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 Ca2+-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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