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Metabolic regulation of neuronal plasticity by the energy sensor AMPK.

Potter WB, O'Riordan KJ, Barnett D, Osting SM, Wagoner M, Burger C, Roopra A - PLoS ONE (2010)

Bottom Line: Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP).These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP.Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

ABSTRACT
Long Term Potentiation (LTP) is a leading candidate mechanism for learning and memory and is also thought to play a role in the progression of seizures to intractable epilepsy. Maintenance of LTP requires RNA transcription, protein translation and signaling through the mammalian Target of Rapamycin (mTOR) pathway. In peripheral tissue, the energy sensor AMP-activated Protein Kinase (AMPK) negatively regulates the mTOR cascade upon glycolytic inhibition and cellular energy stress. We recently demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2DG) alters plasticity to retard epileptogenesis in the kindling model of epilepsy. Reduced kindling progression was associated with increased recruitment of the nuclear metabolic sensor CtBP to NRSF at the BDNF promoter. Given that energy metabolism controls mTOR through AMPK in peripheral tissue and the role of mTOR in LTP in neurons, we asked whether energy metabolism and AMPK control LTP. Using a combination of biochemical approaches and field-recordings in mouse hippocampal slices, we show that the master regulator of energy homeostasis, AMPK couples energy metabolism to LTP expression. Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP). Inhibition of AMPK by either compound-C or the ATP mimetic ara-A rescues the suppression of L-LTP by energy stress. We also show that enhanced LTP via AMPK inhibition requires mTOR signaling. These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP. Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.

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AMPK activation inhibits L-LTP expression.A) AMPK activation inhibits LTP induced by HFS. 10 mM 2DG (n = 10) reduces L-LTP to 10% of control (n = 20) (p = 0.034). 5 µM metformin (n = 8) reduces L-LTP to 40% of control (p = 0.028). B) AMPK activation inhibits LTP induced by TBS. 10 mM 2DG reduces L-LTP (p = 0.022, n = 7) to 30% of control (n = 13), 5 µM metformin reduces L-LTP (p = 0.042, n = 12) to 51% of control. 1 mM AICAR reduces L-LTP (p = 0.0025, n = 8) to 11% of control C) 2DG, metformin and AICAR do not have an effect on basic synaptic transmission. Top: input-output relationships for Schaeffer collateral stimulation and fEPSP slope measured in the presence of ACSF (n = 27), 10 mM 2DG (n = 14), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8). Bottom: Paired Pulse Facilitation is not affected by the presence of 10 mM 2DG (n = 11), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8) compared to ACSF alone (n = 14). Results are plotted as the ratio of fEPSP slopes (2nd stimulus/1st stimulus X100) as a function of interpulse interval (0–300 msec). *p = 0.0002. A and B) Inset: representative fEPSP traces shown were taken 4 minutes prior and 180 minutes after stimulation. Error bars show s.e.m.
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pone-0008996-g003: AMPK activation inhibits L-LTP expression.A) AMPK activation inhibits LTP induced by HFS. 10 mM 2DG (n = 10) reduces L-LTP to 10% of control (n = 20) (p = 0.034). 5 µM metformin (n = 8) reduces L-LTP to 40% of control (p = 0.028). B) AMPK activation inhibits LTP induced by TBS. 10 mM 2DG reduces L-LTP (p = 0.022, n = 7) to 30% of control (n = 13), 5 µM metformin reduces L-LTP (p = 0.042, n = 12) to 51% of control. 1 mM AICAR reduces L-LTP (p = 0.0025, n = 8) to 11% of control C) 2DG, metformin and AICAR do not have an effect on basic synaptic transmission. Top: input-output relationships for Schaeffer collateral stimulation and fEPSP slope measured in the presence of ACSF (n = 27), 10 mM 2DG (n = 14), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8). Bottom: Paired Pulse Facilitation is not affected by the presence of 10 mM 2DG (n = 11), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8) compared to ACSF alone (n = 14). Results are plotted as the ratio of fEPSP slopes (2nd stimulus/1st stimulus X100) as a function of interpulse interval (0–300 msec). *p = 0.0002. A and B) Inset: representative fEPSP traces shown were taken 4 minutes prior and 180 minutes after stimulation. Error bars show s.e.m.

Mentions: Given the necessity of mTOR signaling for L-LTP expression, we predicted that AMPK activation should prevent L-LTP expression. To test this hypothesis, we initially tested the effects of the AMPK activator 2DG on LTP that was induced using 2 different mTOR dependent paradigms: HFS and Theta Burst Stimulation (TBS) [25]. HFS or TBS was delivered between CA1 and CA3 in the Schaeffer Collateral bundle in the presence or absence of 2DG and field excitatory post-synaptic field potentials (fEPSPs) were recorded in the stratum radiatum of CA1. Following either HFS or TBS, the induction step of LTP was indistinguishable between 2DG treated and control slices (Fig. 3A and 3B, respectively), consistent with this step being mTOR independent [7]. However 60 minutes post-stimulation the 2DG-treated slices failed to maintain L-LTP, which falls to 10% of untreated over the course of 3 hours in the HFS paradigm and 30% in the TBS paradigm.


Metabolic regulation of neuronal plasticity by the energy sensor AMPK.

Potter WB, O'Riordan KJ, Barnett D, Osting SM, Wagoner M, Burger C, Roopra A - PLoS ONE (2010)

AMPK activation inhibits L-LTP expression.A) AMPK activation inhibits LTP induced by HFS. 10 mM 2DG (n = 10) reduces L-LTP to 10% of control (n = 20) (p = 0.034). 5 µM metformin (n = 8) reduces L-LTP to 40% of control (p = 0.028). B) AMPK activation inhibits LTP induced by TBS. 10 mM 2DG reduces L-LTP (p = 0.022, n = 7) to 30% of control (n = 13), 5 µM metformin reduces L-LTP (p = 0.042, n = 12) to 51% of control. 1 mM AICAR reduces L-LTP (p = 0.0025, n = 8) to 11% of control C) 2DG, metformin and AICAR do not have an effect on basic synaptic transmission. Top: input-output relationships for Schaeffer collateral stimulation and fEPSP slope measured in the presence of ACSF (n = 27), 10 mM 2DG (n = 14), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8). Bottom: Paired Pulse Facilitation is not affected by the presence of 10 mM 2DG (n = 11), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8) compared to ACSF alone (n = 14). Results are plotted as the ratio of fEPSP slopes (2nd stimulus/1st stimulus X100) as a function of interpulse interval (0–300 msec). *p = 0.0002. A and B) Inset: representative fEPSP traces shown were taken 4 minutes prior and 180 minutes after stimulation. Error bars show s.e.m.
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pone-0008996-g003: AMPK activation inhibits L-LTP expression.A) AMPK activation inhibits LTP induced by HFS. 10 mM 2DG (n = 10) reduces L-LTP to 10% of control (n = 20) (p = 0.034). 5 µM metformin (n = 8) reduces L-LTP to 40% of control (p = 0.028). B) AMPK activation inhibits LTP induced by TBS. 10 mM 2DG reduces L-LTP (p = 0.022, n = 7) to 30% of control (n = 13), 5 µM metformin reduces L-LTP (p = 0.042, n = 12) to 51% of control. 1 mM AICAR reduces L-LTP (p = 0.0025, n = 8) to 11% of control C) 2DG, metformin and AICAR do not have an effect on basic synaptic transmission. Top: input-output relationships for Schaeffer collateral stimulation and fEPSP slope measured in the presence of ACSF (n = 27), 10 mM 2DG (n = 14), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8). Bottom: Paired Pulse Facilitation is not affected by the presence of 10 mM 2DG (n = 11), 5 µM metformin (n = 17) or 1 mM AICAR (n = 8) compared to ACSF alone (n = 14). Results are plotted as the ratio of fEPSP slopes (2nd stimulus/1st stimulus X100) as a function of interpulse interval (0–300 msec). *p = 0.0002. A and B) Inset: representative fEPSP traces shown were taken 4 minutes prior and 180 minutes after stimulation. Error bars show s.e.m.
Mentions: Given the necessity of mTOR signaling for L-LTP expression, we predicted that AMPK activation should prevent L-LTP expression. To test this hypothesis, we initially tested the effects of the AMPK activator 2DG on LTP that was induced using 2 different mTOR dependent paradigms: HFS and Theta Burst Stimulation (TBS) [25]. HFS or TBS was delivered between CA1 and CA3 in the Schaeffer Collateral bundle in the presence or absence of 2DG and field excitatory post-synaptic field potentials (fEPSPs) were recorded in the stratum radiatum of CA1. Following either HFS or TBS, the induction step of LTP was indistinguishable between 2DG treated and control slices (Fig. 3A and 3B, respectively), consistent with this step being mTOR independent [7]. However 60 minutes post-stimulation the 2DG-treated slices failed to maintain L-LTP, which falls to 10% of untreated over the course of 3 hours in the HFS paradigm and 30% in the TBS paradigm.

Bottom Line: Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP).These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP.Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

ABSTRACT
Long Term Potentiation (LTP) is a leading candidate mechanism for learning and memory and is also thought to play a role in the progression of seizures to intractable epilepsy. Maintenance of LTP requires RNA transcription, protein translation and signaling through the mammalian Target of Rapamycin (mTOR) pathway. In peripheral tissue, the energy sensor AMP-activated Protein Kinase (AMPK) negatively regulates the mTOR cascade upon glycolytic inhibition and cellular energy stress. We recently demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2DG) alters plasticity to retard epileptogenesis in the kindling model of epilepsy. Reduced kindling progression was associated with increased recruitment of the nuclear metabolic sensor CtBP to NRSF at the BDNF promoter. Given that energy metabolism controls mTOR through AMPK in peripheral tissue and the role of mTOR in LTP in neurons, we asked whether energy metabolism and AMPK control LTP. Using a combination of biochemical approaches and field-recordings in mouse hippocampal slices, we show that the master regulator of energy homeostasis, AMPK couples energy metabolism to LTP expression. Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP). Inhibition of AMPK by either compound-C or the ATP mimetic ara-A rescues the suppression of L-LTP by energy stress. We also show that enhanced LTP via AMPK inhibition requires mTOR signaling. These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP. Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.

Show MeSH
Related in: MedlinePlus