MOLECULAR BASIS OF LEARNING AND MEMORY

毒品慢性治疗引起的耐受和身体依赖是研究神经元基本可塑性的良好模型。NMDA受体GluRel突变小鼠在重复吗啡治疗后出现明显的镇痛耐受丧失。在中脑导水管周围灰质和腹侧被盖区通过电穿孔的区域特异性拯救GluRel显著逆转了吗啡镇痛耐受的倾向。同样，伏隔核的特异性拯救逆转了GluRel突变小鼠因纳洛酮而导致的身体依赖的丧失。经典的眨眼条件反射，一种简单的联想学习形式，提供了一个实验系统来解决分子、神经信号、突触可塑性、神经回路和行为的复杂关系。根据条件刺激和非条件刺激之间的时间关系，有两种眨眼条件作用的范例。在延迟条件反射中，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突变小鼠的学习能力与野生型小鼠一样成功。相比之下，N-甲基-D-天冬氨酸(NMDA)受体GluRel突变小鼠在延迟条件反射中获得了正常的学习能力，但在跟踪条件反射中表现出严重的障碍。这些发现表明，根据条件刺激和非条件刺激的时间关系，眨眼条件反射背后的神经基质是不同的。GluRd2选择性地表达在小脑浦肯野细胞中，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，我们鉴定了DelPhilin和Shank支架蛋白是GluRd2相互作用的分子。抗GluRd2抗体免疫沉淀小脑突触体膜部分的Shank1、SHANK2、Hmer和代谢性GluR1a蛋白。此外，在小脑中，SHANK2与GRIP1相互作用。这些结果表明，GluRd2通过Shank1和SHANK2与代谢性GluRla、AMPA型GluR和三磷酸肌醇受体(IP3R)相互作用，这些都是小脑长期抑郁所必需的。较少

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