Serotonergic Regulation of NMDA Receptor Trafficking and Function in Prefrontal Cortex

  • Eunice Y. Yuen
  • Zhen Yan

Serotonin is synthesized in brain stem raphe nuclei and has widespread projections in the brain. One of the major targets is prefrontal cortex (PFC), which is located anterior of the frontal lobe. PFC transmits information to and from multiple brain regions including cortex, thalamus, hypothalamus, brain stem, basal ganglia, and limbic areas. PFC contains two primary neuronal populations: glutamatergic pyramidal projection neurons (~80%) and GABAergic interneurons (~20%). Working memory, a form of on-line holding and mental manipulation of information, has been found to require the sustained activity of PFC neurons (Goldman-Rakic, 1995). Functional study in primate shows that serotonin enhances firing of some PFC neurons during the delay period of a delayed-response task, a behavioral test for working memory (Williams et al., 2002).


NMDA Receptor NR2B Subunit Microtubule Stability Free Tubulin NMDAR Current 


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  1. Aghajanian GK, Marek GJ (1999) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161-171.CrossRefPubMedGoogle Scholar
  2. Andrade R (1998) Regulation of membrane excitability in the central nervous system by serotonin receptor subtypes. Ann N Y Acad Sci 861:190-203.CrossRefPubMedGoogle Scholar
  3. Araneda R, Andrade R (1991) 5-Hydroxytryptamine2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuro-science 40:399-412.Google Scholar
  4. Baas PW, Qiang L (2005) Neuronal microtubules: when the MAP is the roadblock. Trends Cell Biol 15:183-187.CrossRefPubMedGoogle Scholar
  5. Bernhardt R, Matus A (1984) Light and electron microscopic studies of the distribution of microtubule-associated protein 2 in rat brain: a difference between dendritic and axonal cytoskeletons. J Comp Neurol 226:203-221.CrossRefPubMedGoogle Scholar
  6. Brugg B, Matus A (1991) Phosphorylation determines the binding of microtubule-associated protein 2 (MAP2) to microtubules in living cells. J Cell Biol 114:735-743.CrossRefPubMedGoogle Scholar
  7. Caceres A, Banker G, Steward O, Binder L, Payne M (1984) MAP2 is localized to the den-drites of hippocampal neurons which develop in culture. Brain Res 315:314-318.PubMedGoogle Scholar
  8. Cleveland DW (1982) Treadmilling of tubulin and actin. Cell 28:689-691.CrossRefPubMedGoogle Scholar
  9. Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11:327-335.CrossRefPubMedGoogle Scholar
  10. Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51:7-61.PubMedGoogle Scholar
  11. Edagawa Y, Saito H, Abe K (1998) 5-HT1A receptor-mediated inhibition of long-term poten-tiation in rat visual cortex. Eur J Pharmacol 349:221-224.CrossRefPubMedGoogle Scholar
  12. Feng J, Cai X, Zhao J, Yan Z (2001) Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci 21:6502-6511.PubMedGoogle Scholar
  13. Goldman-Rakic PS (1995) Cellular basis of working memory. Neuron 14:477-485.CrossRefPubMedGoogle Scholar
  14. Goldstein LS (2003) Do disorders of movement cause movement disorders and dementia? Neuron 40:415-425.CrossRefPubMedGoogle Scholar
  15. Gross C, Hen R (2004) The developmental origins of anxiety. Nat Rev Neurosci 5:545-552.CrossRefPubMedGoogle Scholar
  16. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416:396-400.CrossRefPubMedGoogle Scholar
  17. Guillaud L, Setou M, Hirokawa N (2003) KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons. J Neurosci 23:131-140.PubMedGoogle Scholar
  18. Harder JA, Ridley RM (2000) The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys. Neuropharmacology 39:547-552.CrossRefPubMedGoogle Scholar
  19. Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, Tecott LH (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci USA 95:15049-15054.CrossRefPubMedGoogle Scholar
  20. Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6:201-214.CrossRefPubMedGoogle Scholar
  21. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301-1308.PubMedGoogle Scholar
  22. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharma-cology 20:201-225.Google Scholar
  23. Kia HK, Miquel MC, Brisorgueil MJ, Daval G, Riad M, El Mestikawy S, Hamon M, Verge D (1996) Immunocytochemical localization of serotonin1A receptors in the rat central nerv-ous system. J Comp Neurol 365:289-305.CrossRefPubMedGoogle Scholar
  24. Kroeze WK, Roth BL (1998) The molecular biology of serotonin receptors: therapeutic impli-cations for the interface of mood and psychosis. Biol Psychiatry 44:1128-1142.CrossRefPubMedGoogle Scholar
  25. Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512-517.CrossRefPubMedGoogle Scholar
  26. Malenka RC, Nicoll RA (1999) Long-term potentiation--a decade of progress? Science 285:1870-1874.CrossRefPubMedGoogle Scholar
  27. Mansour SJ, Matten WT, Hermann AS, Candia JM, Rong S, Fukasawa K, Vande Woude GF, Ahn NG (1994) Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265:966-970.CrossRefPubMedGoogle Scholar
  28. Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28:402-412.CrossRefPubMedGoogle Scholar
  29. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharma-cology 21:106S-115S.Google Scholar
  30. Penington NJ, Kelly JS (1990) Serotonin receptor activation reduces calcium current in an acutely dissociated adult central neuron. Neuron 4:751-758.CrossRefPubMedGoogle Scholar
  31. Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor 1A knockout: an animal model of anxiety-related disor-der. Proc Natl Acad Sci USA 95:14476-14481.CrossRefPubMedGoogle Scholar
  32. Sakai N, Tanaka C (1993) Inhibitory modulation of long-term potentiation via the 5-HT1A receptor in slices of the rat hippocampal dentate gyrus. Brain Res 613:326-330.CrossRefPubMedGoogle Scholar
  33. Sanchez C, Diaz-Nido J, Avila J (2000) Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog Neurobiol 61:133-168.CrossRefPubMedGoogle Scholar
  34. Schreiber R, De Vry J (1993) 5-HT1A receptor ligands in animal models of anxiety, impulsiv-ity and depression: multiple mechanisms of action? Prog Neuropsychopharmacol Biol Psychiatry 17:87-104.CrossRefPubMedGoogle Scholar
  35. Setou M, Nakagawa T, Seog DH, Hirokawa N (2000) Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288:1796-1802.CrossRefPubMedGoogle Scholar
  36. Sumiyoshi T, Stockmeier CA, Overholser JC, Dilley GE, Meltzer HY (1996) Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia. Brain Res 708:209-214.CrossRefPubMedGoogle Scholar
  37. Tovar KR, Westbrook GL (1999) The incorporation of NMDA receptors with a distinct sub-unit composition at nascent hippocampal synapses in vitro. J Neurosci 19:4180-4188.PubMedGoogle Scholar
  38. Washbourne P, Bennett JE, McAllister AK (2002) Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nat Neurosci 5:751-759.PubMedGoogle Scholar
  39. Wenthold RJ, Prybylowski K, Standley S, Sans N, Petralia RS (2003) Trafficking of NMDA receptors. Annu Rev Pharmacol Toxicol 43:335-358.CrossRefPubMedGoogle Scholar
  40. Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A recep-tors in working memory. J Neurosci 22:2843-2854.PubMedGoogle Scholar
  41. Wong RW, Setou M, Teng J, Takei Y, Hirokawa N (2002) Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc Natl Acad Sci USA 99:14500-14505.CrossRefPubMedGoogle Scholar
  42. Yuen EY, Jiang Q, Chen P, Gu Z, Feng J, Yan Z (2005) Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci 25:5488-5501.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Eunice Y. Yuen
    • 1
  • Zhen Yan
    • 1
  1. 1.Department of Physiology and Biophysics, School of Medicine and BiomedicalState University of New York at BuffaloBuffaloUSA

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