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Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity

Nature Neuroscience volume 12, pages 190–199 (2009)Cite this article

Abstract

The intrinsic properties of neurons that enable them to maintain depolarized, persistently activated states in the absence of sustained input are poorly understood. In short-term memory tasks, individual prefrontal cortical (PFC) neurons can maintain persistent action potential output during delay periods between informative cues and behavioral responses. Dopamine and drugs of abuse alter PFC function and working memory, possibly by modulating intrinsic neuronal properties. Here we used patch-clamp recording of layer 5 PFC pyramidal neurons to identify a postsynaptic depolarization that was evoked by action potential bursts and mediated by metabotropic glutamate receptor 5 (mGluR5). This depolarization occurred in the absence of recurrent synaptic activity and was reduced by a dopamine D1 receptor (D1R) protein kinase A pathway. After behavioral sensitization to cocaine, the depolarization was substantially diminished and D1R modulation was lost. We propose that burst-evoked intrinsic depolarization is a form of short-term cellular memory that is modulated by dopamine and cocaine experience.

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Figure 1: Patch-clamp recording from layer 5 pyramidal PFC neurons showing mGluR-activated dADP and persistent activity.
Figure 2: Patch-clamp recording from layer 5 pyramidal PFC neurons showing response to an ascending and descending input stimulus before and after mGluR activation.
Figure 3: The dAPD requires intracellular Ca2+ and can amplify and convert near-threshold inputs into sustained output only after an initial action potential.
Figure 4: Burst-induced dADP is mediated by mGluR5.
Figure 5: Dopamine reduces mGluR5- and burst-induced dADP through D1R-PKA pathway.
Figure 6: Repeated cocaine exposure reduces mGluR5- and burst-induced dADP and D1R modulation.
Figure 7: Repeated cocaine treatment reduces the mGluR5- and burst-mediated conversion of subthreshold input to suprathreshold action potential output and D1R modulation.

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References

  1. Goldman-Rakic, P.S. Regional and cellular fractionation of working memory. Proc. Natl. Acad. Sci. USA 93, 13473–13480 (1996).

    Article  CAS  Google Scholar 

  2. Funahashi, S. & Takeda, K. Information processes in the primate prefrontal cortex in relation to working memory processes. Rev. Neurosci. 13, 313–345 (2002).

    Article  Google Scholar 

  3. Winstanley, C.A. et al. DeltaFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction. J. Neurosci. 27, 10497–10507 (2007).

    Article  CAS  Google Scholar 

  4. George, O., Mandyam, C.D., Wee, S. & Koob, G.F. Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments. Neuropsychopharmacology 33, 2474–2482 (2008).

    Article  CAS  Google Scholar 

  5. Goldman-Rakic, P.S. Cellular basis of working memory. Neuron 14, 477–485 (1995).

    Article  CAS  Google Scholar 

  6. Seung, H.S. et al. Stability of the memory of eye position in a recurrent network of conductance-based model neurons. Neuron 26, 259–271 (2000).

    Article  CAS  Google Scholar 

  7. Wang, X.J. Synaptic reverberation underlying mnemonic persistent activity. Trends Neurosci. 24, 455–463 (2001).

    Article  CAS  Google Scholar 

  8. Egorov, A.V., Hamam, B.N., Fransén, E., Hasselmo, M.E. & Alonso, A.A. Graded persistent activity in entorhinal cortex neurons. Nature 420, 173–178 (2002).

    Article  CAS  Google Scholar 

  9. Fowler, M.A., Sidiropoulou, K., Ozkan, E.D., Phillips, C.W. & Cooper, D.C. Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent brain. PloS ONE 2, e573 (2007).

    Article  Google Scholar 

  10. Homayoun, H., Stefani, M.R., Adams, B.W., Tamagan, G.D. & Moghaddam, B. Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology 29, 1259–1269 (2004).

    Article  CAS  Google Scholar 

  11. Homayoun, H. & Moghaddam, B. Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors. Cereb. Cortex 16, 93–105 (2006).

    Article  Google Scholar 

  12. Chiamulera, C. et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 4, 873–874 (2001).

    Article  CAS  Google Scholar 

  13. Otani, S. et al. Dopamine receptors and groups I and II mGluRs cooperate for long-term depression induction in rat prefrontal cortex through converging postsynaptic activation of MAP kinases. J. Neurosci. 19, 9788–9802 (1999).

    Article  CAS  Google Scholar 

  14. Greene, C.C., Schwindt, P.C. & Crill, W.E. Properties and ionic mechanisms of a metabotropic glutamate receptor-mediated slow afterdepolarization in neocortical neurons. J. Neurophysiol. 72, 693–704 (1994).

    Article  CAS  Google Scholar 

  15. Hartmann, J. et al. TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 59, 392–398 (2008).

    Article  CAS  Google Scholar 

  16. Groenewegen, H.J. Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography. Neuroscience 24, 379–431 (1988).

    Article  CAS  Google Scholar 

  17. Carr, D.B. & Sesack, S.R. Dopamine terminals synapse on callosal projection neurons in the rat prefrontal cortex. J. Comp. Neurol. 425, 275–283 (2000).

    Article  CAS  Google Scholar 

  18. Watanabe, M., Kodama, T. & Hikosaka, K. Increase of extracellular dopamine in primate prefrontal cortex during a working memory task. J. Neurophysiol. 78, 2795–2798 (1997).

    Article  CAS  Google Scholar 

  19. Phillips, A.G., Ahn, S. & Floresco, S.B. Magnitude of dopamine release in medial prefrontal cortex predicts accuracy of memory on a delayed response task. J. Neurosci. 24, 547–553 (2004).

    Article  CAS  Google Scholar 

  20. Vijayraghavan, S., Wang, M., Birnbaum, S.G., Williams, G.V. & Arnsten, A.F. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat. Neurosci. 10, 376–384 (2007).

    Article  CAS  Google Scholar 

  21. Williams, G.V. & Goldman-Rakic, P.S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572–575 (1995).

    Article  CAS  Google Scholar 

  22. Wang, J. & O'Donnell, P. D(1) dopamine receptors potentiate NMDA-mediated excitability increase in layer 5 prefrontal cortical pyramidal neurons. Cereb. Cortex 11, 452–462 (2001).

    Article  CAS  Google Scholar 

  23. Yang, C.R. & Seamans, J.K. Dopamine D1 receptor actions in layers 5–6 rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration. J. Neurosci. 16, 1922–1935 (1996).

    Article  CAS  Google Scholar 

  24. Dong, Y. et al. Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: adaptations in potassium currents. J. Neurosci. 25, 936–940 (2005).

    Article  CAS  Google Scholar 

  25. Peterson, J.D., Wolf, M.E. & White, F.J. Repeated amphetamine administration decreases D1 dopamine receptor-mediated inhibition of voltage-gated sodium currents in the prefrontal cortex. J. Neurosci. 26, 3164–3168 (2006).

    Article  CAS  Google Scholar 

  26. Young, C.E. & Yang, C.R. Dopamine D1/D5 receptor modulates state-dependent switching of soma-dendritic Ca2+ potentials via differential protein kinase A and C activation in rat prefrontal cortical neurons. J. Neurosci. 24, 8–23 (2004).

    Article  CAS  Google Scholar 

  27. Homayoun, H. & Moghaddam, B. Progression of cellular adaptations in medial prefrontal and orbitofrontal cortex in response to repeated amphetamine. J. Neurosci. 26, 8025–8039 (2006).

    Article  CAS  Google Scholar 

  28. Hanes, D.P. & Schall, J.D. Neural control of voluntary movement initiation. Science 274, 427–430 (1996).

    Article  CAS  Google Scholar 

  29. Rainer, G., Asaad, W.F. & Miller, E.K. Memory fields of neurons in the primate prefrontal cortex. Proc. Natl. Acad. Sci. USA 95, 15008–15013 (1998).

    Article  CAS  Google Scholar 

  30. Rae, M.G. et al. Role of Ca2+ stores in metabotropic l-glutamate receptor-mediated supralinear Ca2+ signaling in rat hippocampal neurons. J. Neurosci. 20, 8628–8636 (2000).

    Article  CAS  Google Scholar 

  31. Nakamura, T. et al. Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials. Neuron 24, 727–737 (1999).

    Article  CAS  Google Scholar 

  32. Cooper, D.C., Chung, S. & Spruston, N. Output-mode transitions are controlled by prolonged inactivation of sodium channels in pyramidal neurons of subiculum. PLoS Biol. 3, e175 (2005).

    Article  Google Scholar 

  33. Gao, W.J., Krimer, L.S. & Goldman-Rakic, P.S. Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proc. Natl. Acad. Sci. USA 98, 295–300 (2001).

    Article  CAS  Google Scholar 

  34. Madeja, M. Do neurons have a reserve of sodium channels for the generation of action potentials? A study on acutely isolated CA1 neurons from the guinea-pig hippocampus. Eur. J. Neurosci. 12, 1–7 (2000).

    Article  CAS  Google Scholar 

  35. Cooper, D.C. et al. Psychostimulant-induced plasticity of intrinsic neuronal excitability in ventral subiculum. J. Neurosci. 23, 9937–9946 (2003).

    Article  CAS  Google Scholar 

  36. Yoshida, M., Fransén, E. & Hasselmo, M.E. mGluR-dependent persistent firing in entorhinal cortex layer III neurons. Eur. J. Neurosci. 28, 1116–1126 (2008).

    Article  Google Scholar 

  37. Montell, C. The TRP superfamily of cation channels. Sci. STKE 2005, re3 (2005).

    Google Scholar 

  38. Lopez-Bendito, G., Shigemoto, R., Fairen, A. & Lujan, R. Differential distribution of group I metabotropic glutamate receptors during rat cortical development. Cereb. Cortex 12, 625–638 (2002).

    Article  CAS  Google Scholar 

  39. Lujan, R. et al. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).

    Article  CAS  Google Scholar 

  40. Hagenston, A.M., Fitzpatrick, J.S. & Yeckel, M.F. mGluR-mediated calcium waves that invade the soma regulate firing in layer V medial prefrontal cortical pyramidal neurons. Cereb. Cortex 18, 407–423 (2008).

    Article  Google Scholar 

  41. Cooper, D.C. The significance of action potential bursting in the brain reward circuit. Neurochem. Int. 41, 333–340 (2002).

    Article  CAS  Google Scholar 

  42. Gaspar, P., Bloch, B. & Le Moine, C. D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Eur. J. Neurosci. 7, 1050–1063 (1995).

    Article  CAS  Google Scholar 

  43. Zhang, X.F., Hu, X.T. & White, F.J. Whole-cell plasticity in cocaine withdrawal: Reduced sodium currents in nucleus accumbens neurons. J. Neurosci. 18, 488–498 (1998).

    Article  Google Scholar 

  44. Bechara, A. et al. Decision-making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers. Neuropsychologia 39, 376–389 (2001).

    Article  CAS  Google Scholar 

  45. Grant, S. et al. Activation of memory circuits during cue-elicited cocaine craving. Proc. Natl. Acad. Sci. USA 93, 12040–12045 (1996).

    Article  CAS  Google Scholar 

  46. Breiter, H.C. et al. Acute effects of cocaine on human brain activity and emotion. Neuron 19, 591–611 (1997).

    Article  CAS  Google Scholar 

  47. McFarland, K., Lapish, C.C. & Kalivas, P.W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 23, 3531–3537 (2003).

    Article  CAS  Google Scholar 

  48. Perlstein, W.M. et al. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am. J. Psychiatry. 158, 1105–1113 (2001).

    Article  CAS  Google Scholar 

  49. Koenigs, M. et al. Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nat. Neurosci. 11, 232–237 (2008).

    Article  CAS  Google Scholar 

  50. Hu, H.Z. et al. 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J. Biol. Chem. 279, 35741–35748 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Huber (University of Texas Southwestern Medical Center at Dallas) for the mGluR1 and mGluR5 wild-type and knockout mice. This work was supported by National Institute on Drug Abuse grant R01-DA24040 (to D.C.C.), NIDA K award K-01DA017750 (to D.C.C.), a NARSAD Young Investigator award (to D.C.C.), National Institute on Drug Abuse institutional training grant T32-DA7290 (to M.A.F.), the Onassis Public Benefit Foundation (to K.S.), a Gulf War Syndrome contract from the US Department of Veterans Affairs and Veterans Affairs IDIQ contract VA549-P-0027 (awarded and administered by the Dallas, Texas, VA Medical Center). This paper is dedicated to the memory of Francis J. White, a close friend and mentor.

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Author notes

  1. Kyriaki Sidiropoulou

    Present address: Present address: Computational Biology Lab, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology–Hellas, Vassilika Vouton, GR71110, Greece.,

  2. Francis J White: Deceased.

Authors and Affiliations

  1. Department of Neuroscience, Rosalind Franklin University of Health and Science/Chicago Medical School, 3333 Green Bay Road, North Chicago, 60064, Illinois, USA

    Kyriaki Sidiropoulou

  2. Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9070, Texas, USA

    Fang-Min Lu, Melissa A Fowler, Christopher Phillips, Emin D Ozkan & Donald C Cooper

  3. Department of Neuroscience and Center for Molecular Neurobiology, Ohio State University, 206 Rightmire Hall, 1060 Carmack Road, Columbus, 43210, Ohio, USA

    Rui Xiao & Michael X Zhu

  4. Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Health and Science/Chicago Medical School, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.,

    Francis J White

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Contributions

K.S., F.-M.L., E.D.O. and D.C.C. conducted the patch-clamp experiments. K.S. and D.C.C. wrote the manuscript. M.A.F. performed behavioral experiments. C.P. carried out immunoblot experiments, and R.X. and M.X.Z. performed calcium imaging experiments in HEK cells. F.J.W. and D.C.C. supervised the project.

Corresponding author

Correspondence to Donald C Cooper.

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Sidiropoulou, K., Lu, FM., Fowler, M. et al. Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat Neurosci 12, 190–199 (2009). https://doi.org/10.1038/nn.2245

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