AMPK in the central nervous system: physiological roles and pathological implications

Rosso, Pamela; Fioramonti, Marco; Fracassi, Anna; Marangoni, Martina; Taglietti, Valentina; Siteni, Silvia; Segatto, Marco

doi:10.2147/rrb.s90858

Cited by 13 publications

(10 citation statements)

References 130 publications

(134 reference statements)

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“…Previous studies have shown that CRBN is the primary target of thalidomide (Ito et al, 2010), a compound known for its teratogenic effects on the developing fetus. ASDs have been associated with fetal exposure to thalidomide at 20 -24 d gestation (Strömland et al, 1994) and variations in CRBN copy number (Pinto et al, 2010). While Crbn KO mice show hippocampal-dependent learning and memory deficits, they do not demonstrate changes in social or repetitive behavior, and, as reported previously by Rajadhyaksha et al (2012), they show unaltered anxiety-like behavior, hallmarks of ASDs.…”

Section: Crbn Ko Mice As a Model Of Idmentioning

confidence: 85%

“…Crbn KO mice showed a significant deficit in LTP during the first 40 min compared to Crbn WT mice (n ϭ 5/genotype). C, Crbn KO mice displayed a deficit in chemical LTP-induced increase in GluA1 protein levels in the PSD, which was rescued by overexpression of human CRBN (n ϭ 5/genotype Inoki et al, 2003;Rosso et al, 2016) and its potential to impact learning, memory, and synaptic deficits (Ma et al, 2014; in Crbn KO mice (Fig. 5A).…”

Section: Crbn Ko Mice Demonstrate Deficits In Hippocampal Long-term Pmentioning

confidence: 98%

“…Crbn KO mice demonstrate downregulation of mTORC1 mRNA translation initiation factors in the hippocampus AMPK regulates dendritic protein synthesis via mTORC1 (Inoki et al, 2003;Hoeffer and Klann, 2010;Rosso et al, 2016) and the eEF2 pathway (Horman et al, 2002;Hardie, 2004), both of which, via regulating initiation and elongation of mRNA translation, respectively, play a critical role in consolidating long-term synaptic plasticity and long-term memory (Graber et al, 2013;Taha et al, 2013). Heightened activity of AMPK has been shown to repress mRNA translation by inhibition of mTORC1 (Inoki et al, 2003).…”

Section: Loss Of Crbn Does Not Induce Activation Of Autophagy In the mentioning

confidence: 99%

“…Under normal conditions, Crbn directly binds the catalytic subunit AMPK, reducing its affinity for its regulatory ␣ subunit, resulting in suppression of its phosphorylation at Thr172 and subsequent activity (Xu et al, 2013;. Heightened activity of AMPK under con-ditions of metabolic stress impairs learning, memory, and synaptic plasticity via coordination of several downstream pathways, including suppression of dendritic mRNA translation through inhibition of mTOR (Inoki et al, 2003;Hoeffer and Klann, 2010;Rosso et al, 2016) and eEF2 kinase pathways (Horman et al, 2002;Hardie, 2004), as well as activation of the unfolded protein response (UPR) (Appenzeller-Herzog and Hall, 2012) and autophagy (Nixon, 2006;Hegde, 2017). These pathways have been linked to neuronal processes, such as long-term potentiation (LTP), dendritic protein synthesis, excitatory/inhibitory (E/I) balance, and spine dysgenesis (Hoeffer and Klann, 2010;Buffington et al, 2014;Santini and Klann, 2014;Mullins et al, 2016), which are dysregulated in disorders with deficits in learning and memory.…”

Section: Introductionmentioning

confidence: 99%

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Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase–mTORC1 Translational Pathway

et al. 2018

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A homozygous nonsense mutation in the cereblon () gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male knock-out () mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knock-out of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior. Cellular studies identify deficits in long-term potentiation at Schaffer collateral CA1 synapses. We further show that is robustly expressed in the mouse hippocampus and mice exhibit hyperphosphorylated levels of AMPKα (Thr172). Examination of processes downstream of AMP-activated protein kinase (AMPK) finds that mice have a selective impairment in mediators of the mTORC1 translation initiation pathway in parallel with lower protein levels of postsynaptic density glutamatergic proteins and higher levels of excitatory presynaptic markers in the hippocampus with no change in markers of the unfolded protein response or autophagy pathways. Acute pharmacological inhibition of AMPK activity in adult mice rescues learning and memory deficits and normalizes hippocampal mTORC1 activity and postsynaptic glutamatergic proteins without altering excitatory presynaptic markers. Thus, this study identifies that loss of results in learning, memory, and synaptic defects as a consequence of exaggerated AMPK activity, inhibition of mTORC1 signaling, and decreased glutamatergic synaptic proteins. Thus, mice serve as an ideal model of intellectual disability to further explore molecular mechanisms of learning and memory. Intellectual disability (ID) is one of the most common neurodevelopmental disorders. The cereblon () gene has been linked to autosomal recessive, nonsyndromic ID, characterized by an intelligence quotient between 50 and 70 but devoid of other phenotypic features, making cereblon an ideal protein for the study of the fundamental aspects of learning and memory. Here, using the cereblon knock-out mouse model, we show that cereblon deficiency disrupts learning, memory, and synaptic function via AMP-activated protein kinase hyperactivity, downregulation of mTORC1, and dysregulation of excitatory synapses, with no changes in social or repetitive behaviors, consistent with findings in the human population. This establishes the cereblon knock-out mouse as a model of pure ID without the confounding behavioral phenotypes associated with other current models of ID.

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Section: Crbn Ko Mice As a Model Of Idmentioning

confidence: 85%

Section: Crbn Ko Mice Demonstrate Deficits In Hippocampal Long-term Pmentioning

confidence: 98%

Section: Loss Of Crbn Does Not Induce Activation Of Autophagy In the mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase–mTORC1 Translational Pathway

et al. 2018

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“…In fact, in these conditions, both the cytosolic 5'-nucleotidase II (NT5C2) and AMP deaminase (AMPD) are allosterically activated by ATP (Figure 2) (Ashby and Holmsen, 1983;Tozzi et al, 2013), therefore AMP is deaminated by AMPD into IMP, which is dephosphorylated into inosine by NT5C2. Conversely, at low energy charge, the accumulation of AMP inside the cell, leads to the activation of a specific AMP-activated protein kinase (AMPK), the main regulator of cellular energy homeostasis (Hardie et al, 2012;Rosso et al, 2016;Peixoto et al, 2017;Liu et al, 2020) (Figure 2). The dephosphorylation of AMP by a high FIGURE 1 | Extra-and intracellular adenosine production.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

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Alteration of the fecal microbiota in Chinese children with autism spectrum disorder

Xie

et al. 2022

Autism Research

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Autism spectrum disorder (ASD) is associated with altered gut microbiota. However, there has been little consensus on the altered bacterial species and studies have had small sample sizes. We aimed to identify the taxonomic composition and evaluate the changes in the fecal microbiota in Chinese children with ASD by using a relatively large sample size. We conducted a case–control study of 101 children with ASD and 103 healthy controls in China. Demographic information and fecal samples were collected, and the V3‐V4 hypervariable regions of the bacterial 16S ribosomal RNA (rRNA) gene were sequenced. The alpha and beta diversities between the two groups were significantly different. After correcting for multiple comparisons, at the phylum level the relative abundances of Actinobacteria and Proteobacteria in the case group were significantly higher than those in the control group. The relative abundance of the Escherichia‐Shigella genus in the case group was significantly higher than that of the control group, and the relative abundance of Blautia and unclassified_f__Lachnospiraceae in the control group were higher than that of the case group. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis showed that children with ASD may have disturbed functional pathways, such as amino acid metabolism, cofactor and vitamin metabolism, and the AMP‐activated protein kinase signaling pathway. This study revealed the characteristics of the intestinal flora of Chinese children with ASD and provided further evidence of gut microbial dysbiosis in ASD. Lay Summary This study characterized the gut microbiota composition of 101 children with ASD and 103 healthy controls in China. The altered gut microbiota may contribute significantly to the risk of ASD, including significant increases in the relative abundances of Actinobacteria, Proteobacteria and Escherichia‐Shigella and significant decrease of Blautia and unclassified_f__Lachnospiraceae. This study provided further evidence of gut microbial dysbiosis in ASD.

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AMPK in the central nervous system: physiological roles and pathological implications

Cited by 13 publications

References 130 publications

Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase–mTORC1 Translational Pathway

Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase–mTORC1 Translational Pathway

Metabolic Aspects of Adenosine Functions in the Brain

Alteration of the fecal microbiota in Chinese children with autism spectrum disorder

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