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Spatial Memory Formation and Memory-Enhancing Effect of Glucose Involves Activation of the Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway

Dash, Pramod K., Orsi, Sara A., Moore, Anthony N.·2006·The Journal of Neuroscience

Abstract

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-1β-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.

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Crossref · 10.1523/jneurosci.0671-06.2006

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Figure 1 Intrahippocampal infusion of rapamycin decreases S6K phosphorylation. Shown are representative images of immunoreactivity for phosphorylated S6K within the CA1/CA2 subfield of the hippocampus after intrahippocampal vehicle ( A , C , E ) or rapamycin ( B , D , F ) infusion. A , B , Core of the infusion. C , D , At 1.5 mm caudal to the infusion site. E , F , Ventral hippocampus. Scale bar, 100 𝛍 m.
Figure 1 Intrahippocampal infusion of rapamycin decreases S6K phosphorylation. Shown are representative images of immunoreactivity for phosphorylated S6K within the CA1/CA2 subfield of the hippocampus after intrahippocampal vehicle ( A , C , E ) or rapamycin ( B , D , F ) infusion. A , B , Core of the infusion. C , D , At 1.5 mm caudal to the infusion site. E , F , Ventral hippocampus. Scale bar, 100 𝛍 m.CC-BY-NC-SA · From the PDF
Image 2
CC-BY-NC-SA · From the PDF
Figure 5 AICAR decreases mTOR activity and impairs long-term spatial memory. A , Representative Western blots and summary data showing that intrahippocampal administration of 260 ng of AICAR decreases phospho-S6K and phospho-4EBP1, but not total S6K or 4EBP1, immunoreactivities at 30 min after infusion as compared with the contralateral vehicle-infused hippocampus. B , Latencies during water maze training and probe trial for animals infused with either vehicle ( n = 8) or 260 ng/hippocampus AICAR ( n = 9). C , Representative probe trial traces of a vehicle-infused and an AICAR-infused animal showing the path taken before the first platform crossing. AICAR-infused animals had an increased mean distance traveled ( D ) and a decreased number of platform crossings ( E ) during the probe trial. F , Swimming speed was not different between the two groups. Data are presented as the mean ± SEM; * p < 0.05.
Figure 5 AICAR decreases mTOR activity and impairs long-term spatial memory. A , Representative Western blots and summary data showing that intrahippocampal administration of 260 ng of AICAR decreases phospho-S6K and phospho-4EBP1, but not total S6K or 4EBP1, immunoreactivities at 30 min after infusion as compared with the contralateral vehicle-infused hippocampus. B , Latencies during water maze training and probe trial for animals infused with either vehicle ( n = 8) or 260 ng/hippocampus AICAR ( n = 9). C , Representative probe trial traces of a vehicle-infused and an AICAR-infused animal showing the path taken before the first platform crossing. AICAR-infused animals had an increased mean distance traveled ( D ) and a decreased number of platform crossings ( E ) during the probe trial. F , Swimming speed was not different between the two groups. Data are presented as the mean ± SEM; * p < 0.05.CC-BY-NC-SA · From the PDF
Figure 6 Post-training administration of glucose cannot overcome the memory impairmentcausedbythecoadministration of rapamycin. A , Performance during training and testing in the water maze task for animals infused with either 0.9 ng of rapamycin/hippocampus or 0.9 ngofrapamycinplus20 𝛍 gofglucose/hippocampus.ErrorbarsindicateSEM. B , Representative photomicrograph of a cresyl violet-stained tissue section showing the infusion track in one of the cannulated animals used in the behavioral studies. C , Illustration indicating the infusion sites (black circles) for the animals used in the behavioral studies. Non-redundant infusion sites are shown.
Figure 6 Post-training administration of glucose cannot overcome the memory impairmentcausedbythecoadministration of rapamycin. A , Performance during training and testing in the water maze task for animals infused with either 0.9 ng of rapamycin/hippocampus or 0.9 ngofrapamycinplus20 𝛍 gofglucose/hippocampus.ErrorbarsindicateSEM. B , Representative photomicrograph of a cresyl violet-stained tissue section showing the infusion track in one of the cannulated animals used in the behavioral studies. C , Illustration indicating the infusion sites (black circles) for the animals used in the behavioral studies. Non-redundant infusion sites are shown.CC-BY-NC-SA · From the PDF
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CC-BY-NC-SA · From the PDF

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Metadata

Authors
Dash, P. K., Orsi, S. A., & Moore, A. N.
Venue
The Journal of Neuroscience
Published
2006-08-02
Volume
26
Issue
31
Pages
8048-8056
ISSN
  • 0270-6474
  • 1529-2401
Cited by
141
References
8
Language
en

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