MOLECULAR BASIS OF LEARNING AND MEMORY

慢性麻醉品治疗引起的耐受性和身体依赖性是研究基础神经元可塑性的良好模型。NMDA受体glrel突变小鼠在多次吗啡治疗后表现出明显的镇痛耐受性丧失。导水管周围灰质和腹侧被盖区电穿孔对GluRel的区域特异性拯救显著逆转吗啡镇痛耐受倾向。同样，伏隔核特异性救援逆转了glrel突变小鼠因纳洛酮引起的身体依赖性的丧失。经典的眨眼条件反射是联想学习的一种简单形式，为解决分子、神经信号、突触可塑性、神经回路和行为之间的复杂关系提供了一个实验系统。根据条件刺激和非条件刺激之间的时间关系，眨眼条件反射有两种范式。在延迟条件作用中，小脑浦肯野细胞特异性GluRd2突变小鼠表现出更严重的学习障碍。然而，在跟踪范式中，GluRd2突变小鼠与野生型小鼠一样成功地学习。相比之下，n -甲基- d -天冬氨酸（NMDA）受体glrel突变小鼠在延迟条件反射中获得正常水平的学习，但在微量条件反射中表现出严重的损伤。这些发现表明，根据条件刺激和非条件刺激的时间关系，眨眼条件反射的神经基质是不同的。GluRd2在小脑浦肯野细胞中选择性表达，在小脑长期抑郁、运动学习和平行纤维突触的形成中起核心作用。通过酵母双杂交筛选，我们确定了Delphilin和Shank支架蛋白是glurd2的相互作用分子。抗glurd2抗体免疫沉淀来自小脑突触体膜部分的Shank1， Shank2， Homer和代谢性GluRla蛋白。此外，Shank2在小脑中与GRIP1相互作用。这些结果表明，通过Shank1和Shank2， GluRd2与代谢代谢GluRla、ampa型GluR和肌醇1,4,5-三磷酸受体（IP3R）相互作用，这是小脑长期抑郁所必需的。少

Tolerance and physical dependence caused by chronic treatment of narcotics are good models to study basic neuronal plasticity. NMDA receptor GluRel mutant mice showed a marked loss of the analgesic tolerance after repeated morphine treatments. Region-specific rescue of GluRel by electroporation in the periaqueductal gray matter and the ventral tegmental area significantly reversed morphine analgesic tolerance liability. Similarly, nucleus accumbens-specific rescue reversed the loss of naloxone-precipitated physical dependence in GluRel mutant mice.Classical eyeblink conditioning, a simple form of associative learning, provides an experimental system to solve the complex relationships of molecules, neural signaling, synaptic plasticity, neural circuits and behaviors. There are two paradigms of eyeblink conditioning depending on the temporal relationship between the conditioned and unconditioned stimuli. In delay conditioning, cerebellar Purkinje cell-specific GluRd2 mutant mice exhibite … More d a severe impairment in learning. However, in the trace paradigm, GluRd2 mutant mice learned as successfully as the wild-type mice. In contrast, N-methyl-D-aspartate (NMDA) receptor GluRel mutant mice attained a normal level of learning in delay conditioning, but exhibited severe impairment in trace conditioning. These findings suggest that neural substrates underlying eyeblink conditioning are distinct depending on the temporal relationships of the conditioned and unconditioned stimuli.GluRd2 selectively expressed in cerebellar Purkinje cells plays a central role in cerebellar long-term depression, motor learning and formation of parallel fiber synapses. By yeast two- hybrid screening, we identified Delphilin and Shank scaffold proteins as GluRd2-interacting molecules. Anti-GluRd2 antibodies immunoprecipitated Shank1, Shank2, Homer and metabotropic GluRla proteins from the synaptosomal membrane fractions of cerebella. Furthermore, Shank2 interacted with GRIP1 in the cerebellum. These results suggest that through Shank1 and Shank2, GluRd2 interacts with the metabotropic GluRla, the AMPA-type GluR and the inositol 1,4,5-trisphosphate receptor (IP3R) that are essential for cerebellar long- term depression. Less