| Co-Investigator(Kenkyū-buntansha) |
TAKEUCHI Tomonori UNIVERSITY OF TOKYO, MOLECULAR NEUROBIOLOGY, ASSISTANT PROFESSOR, 医学系研究科, 助手 (50323613)
MORI Hisashi UNIVERSITY OF TOKYO, MOLECULAR NEUROBIOLOGY, LECTURER, 医学系研究科, 講師 (00239617)
MATSUDA Naoto UNIVERSITY OF TOKYO, MOLECULAR NEUROBIOLOGY, ASSISTANT PROFESSOR, 医学系研究科, 助手 (40313100)
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| Research Abstract |
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
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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
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