Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-mammalian target of rapamycin pathway

被引:131
作者
Dash, Pramod K.
Orsi, Sara A.
Moore, Anthony N.
机构
[1] Univ Texas, Sch Med, Dept Neurobiol & Anat, Houston, TX 77225 USA
[2] Univ Texas, Sch Med, Vivian L Smith Ctr Neurol Res, Houston, TX 77225 USA
关键词
AICAR; glucose; hippocampus; rapamycin; spatial memory; tuberous sclerosis complex;
D O I
10.1523/JNEUROSCI.0671-06.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The tuberous sclerosis complex-mammalian target of rapamycin (TSC- mTOR) cascade integrates growth factor and nutritional signals to regulate the synthesis of specific proteins. Because both growth factor signaling and glucose have been implicated in memory formation, we questioned whether mTOR activity is required for long-term spatial memory formation and whether this cascade is involved in the memory-augmenting effect of centrally applied glucose. To test our hypothesis, we directly administered rapamycin ( an inhibitor of mTOR), glucose, 5-aminoimidazole-4-carboxamide-1 beta-4-ribonucleoside ( AICAR; an activator of AMP kinase), or glucose plus rapamycin into the dorsal hippocampus after we trained rats in the Morris water maze task. The results from these studies indicate that glucose enhances, whereas AICAR and rapamycin both impair, long-term spatial memory. Furthermore, the memory- impairing effect of targeted rapamycin administration could not be overcome by coadministration of glucose. Consistent with these behavioral results, biochemical analysis revealed that glucose and AICAR had opposing influences on the activation of the TSC- mTOR cascade, as indicated by the phosphorylation of ribosomal S6 kinase (S6K) and 4E binding protein 1 (4EBP1), targets of mTOR. Together, these findings suggest that memory formation requires the mTOR cascade and that the memory- enhancing effect of glucose involves its ability to activate this pathway.
引用
收藏
页码:8048 / 8056
页数:9
相关论文
共 67 条
[1]   The MAPK cascade is required for mammalian associative learning [J].
Atkins, CM ;
Selcher, JC ;
Petraitis, JJ ;
Trzaskos, JM ;
Sweatt, JD .
NATURE NEUROSCIENCE, 1998, 1 (07) :602-609
[2]   EFFECTS OF GLUCOSE ON MEMORY PROCESSES IN YOUNG-ADULTS [J].
AZARI, NP .
PSYCHOPHARMACOLOGY, 1991, 105 (04) :521-524
[3]   STRUCTURAL-CHANGES ACCOMPANYING MEMORY STORAGE [J].
BAILEY, CH ;
KANDEL, ER .
ANNUAL REVIEW OF PHYSIOLOGY, 1993, 55 :397-426
[4]   The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors [J].
Beck, T ;
Hall, MN .
NATURE, 1999, 402 (6762) :689-692
[5]  
Berman DE, 1998, J NEUROSCI, V18, P10037
[6]  
Blum S, 1999, J NEUROSCI, V19, P3535
[7]   A cell-permeable phospholipase Cγ1-binding peptide transduces neurons and impairs long-term spatial memory [J].
Blum, S ;
Dash, PK .
LEARNING & MEMORY, 2004, 11 (03) :239-243
[8]   AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. [J].
Bolster, DR ;
Crozier, SJ ;
Kimball, SR ;
Jefferson, LS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (27) :23977-23980
[9]   Immediate response of mammalian target of rapamycin (mTOR)-mediated signalling following acute resistance exercise in rat skeletal muscle [J].
Bolster, DR ;
Kubica, N ;
Crozier, SJ ;
Williamson, DL ;
Farrell, PA ;
Kimball, SR ;
Jefferson, LS .
JOURNAL OF PHYSIOLOGY-LONDON, 2003, 553 (01) :213-220
[10]   Glucose injections into the dorsal hippocampus or dorsolateral striatum of rats prior to T-maze training: Modulation of learning rates and strategy selection [J].
Canal, CE ;
Stutz, SJ ;
Gold, PE .
LEARNING & MEMORY, 2005, 12 (04) :367-374