Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 23, Pages 5488-5501Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1187-05.2005
Keywords
trafficking; KIF17; MAP2; Ca2+/calmodulin-dependent kinase II; MAP kinase; prefrontal cortex; siRNA; antisense oligonucleotides
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Funding
- NIA NIH HHS [AG21923, R01 AG021923] Funding Source: Medline
- NIMH NIH HHS [MH63128, R01 MH063128] Funding Source: Medline
- NINDS NIH HHS [R01 NS048911, NS48911] Funding Source: Medline
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The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT1A receptors. This effect of 5-HT1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT1A-NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.
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