Yuen Eunice Y, Jiang Qian, Chen Paul, Gu Zhenglin, Feng Jian, Yan Zhen
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
J Neurosci. 2005 Jun 8;25(23):5488-501. doi: 10.1523/JNEUROSCI.1187-05.2005.
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-HT(1A) 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-HT(1A) receptors. This effect of 5-HT(1A) 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-HT(1A) modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT(1A) activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT(1A) 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-HT(1A)-NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.
前额叶皮质（PFC）中的5-羟色胺系统和N-甲基-D-天冬氨酸受体（NMDARs）在正常和病理条件下均对认知和情绪的调节起着关键作用；然而，它们之间的相互作用基本上尚不清楚。在此我们表明，5-羟色胺通过激活5-HT（1A）受体，抑制了PFC锥体神经元中NMDAR介导的离子电流和突触电流，且含NR2B亚基的NMDAR是5-HT（1A）受体的主要作用靶点。5-HT（1A）受体的这种作用被干扰微管组装的药物以及通过细胞敲低驱动蛋白KIF17（驱动蛋白超家族成员17）所阻断，KIF17可沿神经元树突中的微管运输含NR2B的囊泡。抑制钙/钙调蛋白依赖性激酶II（CaMKII）或丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（MEK/ERK）均可消除5-HT（IA）对NMDAR电流的调节作用。生化证据还表明，5-HT（1A）激活降低了微管稳定性，而CaMKII或MEK抑制剂可消除这种作用。此外，免疫细胞化学研究表明，5-HT（1A）激活减少了树突上表面NR2B亚基的数量，而微管稳定剂可阻止这种减少。总之，这些结果表明，5-羟色胺通过一种依赖于基于微管/驱动蛋白的NMDAR树突运输的机制来抑制NMDAR功能，该机制受CaMKII和ERK信号通路调节。5-HT（1A）-NMDAR相互作用为5-羟色胺在控制PFC所支持的情绪和认知过程中的作用提供了一种潜在机制。
