打孩子时,家长常常会说,“下次记住疼!”这或许有点道理。美国科学家的一项最新研究首次表明,能够影响机体痛觉的神经受体TRPV1在大脑的学习和记忆中也起到特定作用。这一研究成果有望为治疗记忆损失和癫痫症提供新的药物标靶。相关论文发表在3月13日的《神经元》(Neuron)杂志上。
TRPV1全称为瞬时受体电位香草酸亚型(transient receptor potential vanilloid subtype),它们普遍分布于包括皮肤、脊髓和大脑在内的神经系统中。该类受体能够感知热量、引发炎症并传导疼痛。此外,它们还能够对辣椒素做出响应。
在最新的研究中,美国布朗大学医学教授Julie Kauer和她的小组发现,TRPV1受体的活化能够引起长时程抑制(long-term depression,简称LTD),从而导致神经元突触联接的永久改变。而这些大脑改变,以及相应的神经重组和长期增益(long-term potentiation)过程往往被认为是细胞层面上记忆形成的基础。
利用辣椒素处理小鼠海马区(与学习和记忆相关的大脑区域)脑组织后,研究人员发现,TRPV1通道被激活,且该通道的单独作用就可引起长时程抑制。同时,一种名为利莫那班(Rimonabant)的药物可以通过关闭TRPV1通道来完全阻断这种压抑状态。随后,研究人员又对去除TRPV1受体的小鼠大脑组织进行了类似的研究,结果没有发现长时程抑制现象。
Kauer表示,“新揭示的TRPV1受体功能是出乎我们意料的。此前,从没有人将这一疼痛受体与记忆的深层机制联系起来。因此可以说,我们发现了大脑神经可塑性的一个全新角色。”
新的研究成果有望为阻止记忆损失以及治疗神经系统紊乱提供有效的药物标靶。此外,Kauer表示,新结论还具有警示意义。用于治疗肥胖的利莫那班会阻碍TRPV1受体,此外,还有许多止痛剂和消炎药也是通过影响TRPV1起作用。但值得注意的是,这些与中央神经系统的TRPV1受体绑定的药物起到的作用很可能不仅仅是止痛而已。“新的发现表明,这些药物可能会有一些精神病方面的副作用。”Kauer说。(科学网 任霄鹏/编译)
生物谷推荐原始出处:
(Neuron),Vol 57, 746-759, 13 March 2008,Helen E. Gibson, Julie A. Kauer
TRPV1 Channels Mediate Long-Term Depression at Synapses on Hippocampal Interneurons
Helen E. Gibson,1,2 Jeffrey G. Edwards,1,2,3 Rachel S. Page,1 Matthew J. Van Hook,1 and Julie A. Kauer1,
1 Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA
Corresponding author
Summary
TRPV1 receptors have classically been defined as heat-sensitive, ligand-gated, nonselective cation channels that integrate nociceptive stimuli in sensory neurons. TRPV1 receptors have also been identified in the brain, but their physiological role is poorly understood. Here we report that TRPV1 channel activation is necessary and sufficient to trigger long-term synaptic depression (LTD). Excitatory synapses onto hippocampal interneurons were depressed by either capsaicin, a potent TRPV1 channel activator, or the endogenously released eicosanoid, 12-(S)-HPETE, whereas neighboring excitatory synapses onto CA1 pyramidal cells were unaffected. TRPV1 receptor antagonists also prevented interneuron LTD. In brain slices from TRPV1−/− mice, LTD was absent, and neither capsaicin nor 12-(S)-HPETE elicited synaptic depression. Our results suggest that, in the hippocampus, TRPV1 receptor activation selectively modifies synapses onto interneurons. Like other forms of hippocampal synaptic plasticity, TRPV1-mediated LTD may have a role in long-term changes in physiological and pathological circuit behavior during learning and epileptic activity.