Li Shanshan, Geiger Jonathan D, Lei Saobo
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58202, USA.
J Neurophysiol. 2008 May;99(5):2134-43. doi: 10.1152/jn.00890.2007. Epub 2008 Mar 12.
Neurotensin (NT) is a tridecapeptide that interacts with three NT receptors; NTS1, NTS2, and NTS3. Although NT has been reported to modulate GABAergic activity in the brain, the underlying cellular and molecular mechanisms of NT are elusive. Here, we examined the effects of NT on GABAergic transmission and the involved cellular and signaling mechanisms of NT in the hippocampus. Application of NT dose-dependently increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal neurons with no effects on the amplitude of sIPSCs. NT did not change either the frequency or the amplitude of miniature (m)IPSCs recorded in the presence of tetrodotoxin. Triple immunofluorescent staining of recorded interneurons demonstrated the expression of NTS1 on GABAergic interneurons. NT increased the action potential firing rate but decreased the afterhyperpolarization (AHP) amplitude in identified CA1 interneurons. Application of L-type calcium channel blockers (nimodipine and nifedipine) abolished NT-induced increases in action potential firing rate and sIPSC frequency and reduction in AHP amplitude, suggesting that the effects of NT are mediated by interaction with L-type Ca(2+) channels. NT-induced increase in sIPSC frequency was blocked by application of the specific NTS1 antagonist SR48692, the phospholipase C (PLC) inhibitor U73122, the IP(3) receptor antagonist 2-APB, and the protein kinase C inhibitor GF109203X, suggesting that NT increases gamma-aminobutyric acid release via a PLC pathway. Our results provide a cellular mechanism by which NT controls GABAergic neuronal activity in hippocampus.
神经降压素（NT）是一种十三肽，可与三种NT受体相互作用，即NTS1、NTS2和NTS3。尽管已有报道称NT可调节大脑中的GABA能活性，但其潜在的细胞和分子机制仍不清楚。在此，我们研究了NT对海马体中GABA能传递的影响以及NT所涉及的细胞和信号传导机制。应用NT可剂量依赖性地增加从CA1锥体神经元记录到的自发性抑制性突触后电流（sIPSCs）的频率，而对sIPSCs的幅度没有影响。NT对在河豚毒素存在下记录的微小（m）IPSCs的频率或幅度均无改变。对记录的中间神经元进行三重免疫荧光染色显示，NTS1在GABA能中间神经元上表达。NT增加了已鉴定的CA1中间神经元的动作电位发放率，但降低了超极化后电位（AHP）的幅度。应用L型钙通道阻滞剂（尼莫地平和硝苯地平）消除了NT诱导的动作电位发放率和sIPSC频率的增加以及AHP幅度的降低，这表明NT的作用是通过与L型Ca（2+）通道相互作用介导的。应用特异性NTS1拮抗剂SR48692、磷脂酶C（PLC）抑制剂U73122、IP（3）受体拮抗剂2-APB和蛋白激酶C抑制剂GF109203X可阻断NT诱导的sIPSC频率增加，这表明NT通过PLC途径增加γ-氨基丁酸的释放。我们的结果提供了一种细胞机制，通过该机制NT可控制海马体中GABA能神经元的活动。
