NR2B-containing N-methyl-D-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo

Behavioral stress facilitates long-term depression but impairs long-term potentiation in the hippocampus. Recent evidence in vitro demonstrates that the NIR2B-containing N-methyl-D-aspartate subtype glutamate receptor antagonist Ro25-6981 prevents the beh

Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death

Acid-sensing ion channels (ASICs) composed of ASIC1a subunit exhibit a high Ca2+ permeability and play important roles in synaptic plasticity and acid-induced cell death. Here, we show that ischemia enhances ASIC currents through the phosphorylation at Ser478 and Ser479 of ASIC1a, leading to exacerbated ischemic cell death. The phosphorylation is catalyzed by Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, as a result of activation of NR2B-containing N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) during ischemia. Furthermore, NR2B-specific antagonist, CaMKII inhibitor, or overexpression of mutated form of ASIC1a with Ser478 or Ser479 replaced by alanine (ASICla-S478A, ASIC1a-S479A) in cultured hippocampal neurons prevented ischemia-induced enhancement of ASIC currents, cytoplasmic Ca2+ elevation, as well as neuronal death. Thus, NMDAR-CaMKII cascade is functionally coupled to ASICs and contributes to acidotoxicity during ischemia. Specific blockade of NMDAR/CaMKII-ASIC coupling may reduce neuronal death after ischemia and other pathological conditions involving excessive glutamate release and acidosis.

海马在情绪记忆中的作用

海马是中脑边缘系统的一个重要区域，不仅在学习和记忆中起着重要作用， 还在应激调控中起着关键作用。越来越多的报道表明，海马可能参与毒品成瘾。 本文围绕海马与成瘾、海马与应激的相互关系，应用行为学及电生理技术手段探 讨了海马在成瘾中的作用，并对应激的作用机制进行了研究。 第一部分试验首先研究了长期成瘾药物暴露对两种不同类型学习记忆的影 响，从而揭示成瘾对不同脑区的影响；我们还研究了长期毒品戒断对学习和记忆 的影响。用条件化位置偏爱/厌恶模型对海马在成瘾相关记忆中的作用进行了探 讨。实验结果提示，在成瘾过程中不同脑区发生了不同程度的适应性改变，从而 影响了该脑区相关的正常学习和记忆，其中慢性吗啡暴露损伤了海马依赖的空间 记忆提取，但长期戒断（戒断5 个星期）可以缓解成瘾导致的这些影响。另外， 海马在成瘾相关记忆中同样发挥了重要作用。吗啡偏爱形成后的环境线索再暴露 损伤海马突触长时程增强，提示了海马在环境线索诱导的药物渴求和复吸中可能 起着关键性作用。 第二部分试验主要探索了应激效应的作用机制及海马VR1 受体对抗应激效 应。发现含NR2B 的NMDA 受体参与了应激导致的海马突触可塑性改变，其阻 断剂Ro25-6981 阻断了应激易化的海马长时程抑制，避免了应激损伤的长时程增 强。另一方面，应激损伤海马依赖性的空间记忆提取，但是辣椒素(VR1 受体的 激动剂)直接注射入海马能逆转这种应激的损伤效应。相反，VR1 受体拮抗剂 capsazepin 处理产生了类似应激的损伤效应。提示了海马内VR1 受体可能是海马 记忆功能的一种重要受体系统。