Metformin target AMPK shown for the first time to be required for Long-Term Memory Formation: Hypothesis Substantiated

By Davidboyashi - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=48165329

 A recently published study in the journal iScience in October of 2018 demonstrated for the first time that metabolic plasticity induced by AMPK activation is required for long-term potentiation (LTP) in the CA1 region of the hippocampus in vitro in mouse neurons as well as long-term memory formation in vivo in mice [1]. These results provide direct support and substantiate my previous hypothesis in which I first proposed that activation of AMPK will promote LTP specifically in the CA1 region of the hippocampus and promote memory formation in vivo [2]. AMPK activation is considered a primary mechanism through which the anti-diabetic drug metformin and numerous naturally-occurring compounds exert their therapeutic effects [3]. Learning and memory are generally considered the behavioral correlates of long-term potentiation (LTP), a form of synaptic plasticity associated with a persistent and long-lasting increase in synaptic strength in response to repetitive neuronal stimulation [2]. It is the Schaffer collateral-CA1 excitatory synapse (i.e. CA1 synapses) that has generated increased interest in recent years due to accumulating evidence that high frequency stimulation of CA1 synapses leads to a long–lasting increase in synaptic strength that underlies learning and memory [2]. In the iScience study, Marinangeli et al. initially demonstrated that synaptic activation of primary mouse neurons with a combination of bicuculline and 4-aminopyridine rapidly activated AMPK. AMPK activation was dependent on glutamate receptor activation, as the NMDA and AMPA receptor inhibitors MK-801 and NBQX, respectively, significantly reduced AMPK activation [1].

Inhibition of AMPK by compound C or a kinase-dead dominant-negative AMPK construct also significantly decreased ATP levels and the upregulation of glycolysis and mitochondrial respiration, indicating that AMPK is critical for maintaining neuronal energy levels in response to synaptic activation [1]. Interestingly, AMPK inhibition also significantly reduced the expression of the immediate-early genes Arc, cFos, and Egrl (important for learning and memory), indicating that AMPK activation is required for the expression of these genes following synaptic activation. Importantly, inhibition of AMPK by compound C severely impaired LTP in the CA1 region of the hippocampus induced by electrical theta burst stimulation [1]. The authors also determined if AMPK activation is necessary for long-term memory retention in vivo in mice. Bilateral injection of compound C in the hippocampus before inhibitory avoidance training significantly blocked long-term memory tested at 24 hours which persisted after retesting at 6 days, providing compelling evidence that AMPK activation is critical for CA1 LTP in vitro and long-term memory formation in vivo [1].

As noted above, I first proposed in April of 2018 that AMPK activation would promote LTP specifically in area CA1 of the hippocampus and enhance learning and memory in vivo [2]. Indeed, the authors of the iScience study performed precise experiments that verified and substantiated my hypothesis, as follows: “Knockdown or pharmacological inhibition of both AMPK catalytic subunits (AMPKα1 and AMPKα2) in hippocampal neurons (e.g. hippocampal CA1 pyramidal neurons) would be conducted to determine if AMPK activation is essential for the induction, expression, and/or maintenance of LTP in vitro or the facilitation of learning and memory in vivo.” [2]. I also proposed in this paper that cellular stress-induced AMPK activation links CA1 LTP with the reactivation of latent HIV-1, facilitating immune system detection and potential destruction of the virus [2]. Intriguingly, the iScience study showed that AMPK increased the expression of the immediate-early gene Egr1 whereas the AMPK activator resveratrol reactivates latent HIV-1 via upregulation of Egr-1 [3,4]. Egr-1 was shown to be downregulated during viral latency in HIV-1 infected ACH-2 cells and treatment with resveratrol caused viral reactivation as indicated by a dose-dependent increase in viral p24 expression, suggesting that AMPK activation may indeed facilitate reactivation and destruction of the virus [2,4].

The iScience study also showed that AMPK activation increased the expression of the immediate-early gene Arc. Arc plays a critical role in memory formation and has recently been shown to be derived from a transposable element, DNA sequences first described by Nobel laureate Barbara McClintock that comprise nearly half of the human genome and are able to transpose or move from one genomic location to another [5,6]. I also recently proposed for the first time that AMPK activation would promote beneficial activation and transposition of transposable elements (also known as “jumping genes”) located in the human brain, human sperm, and in human oocytes [6]. Indeed, the transposable element L1 is present in the hippocampus of the human brain and contributes to memory formation in vivo in mice [7,8]. Additionally, metformin promotes AMPK-dependent telomerase activation (critical for telomere maintenance) and induces activation of the endonuclease RAG1 (promotes DNA cleavage and transposition) via AMPK [9,10]. Similar to Arc, both RAG1 and telomerase are derived from transposable elements, providing further evidence that AMPK links learning and memory with potential HIV-1 eradication and transposable element activation and mobilization [2,6,11].

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References:

1.  Marinangeli C, Didier S, Ahmed T, et al. AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels during Synaptic Activation. iScience. 2018 Oct 12;9:1-13. doi: 10.1016/j.isci.2018.10.006. [Epub ahead of print].
2. Finley J. Facilitation of hippocampal long-term potentiation and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking learning, memory, and the potential eradication of HIV-1. Med Hypotheses. 2018 Jul;116:61-73.
3. Hardie DG. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes 2013;62(7):2164–72.
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9. Karnewar S, Neeli PK, Panuganti D, et al. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: relevance in age-associated vascular dysfunction. Biochim Biophys Acta 2018;1864(4 Pt A):1115–28.
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