title: AMPK activation regulates neuronal structure in developing hippocampal neurons.
abstract: AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a cellular and whole organism energy sensor to regulate ATP-consuming (anabolic) and ATP-generating (catabolic) pathways. The heterotrimeric AMPK complex consists of a catalytic α-subunit, regulatory β-subunit, and an AMP/ATP-binding γ-subunit. Several alternate isoforms exist for each subunit (α1, α2, β1, β2, γ1, γ2 and γ3). However, little is known of the expression pattern or function of the individual catalytic complexes in regulating neuronal structure. In this study, we examined the role of AMPK subunits in differentiating hippocampal neurons. We found that during development, the expression of AMPK subunits increase and that activation of AMPK by energetic stress inhibits neuronal development at multiple stages, not only during axon outgrowth, but also during dendrite growth and arborization. The presence of a single functional AMPK catalytic complex was sufficient to mediate these inhibitory effects of energetic stress. Activation of AMPK mediates these effects by suppressing both the mTOR and Akt signaling pathways. These findings demonstrate that the energy-sensing AMPK pathway regulates neuronal structure in distinct regions of developing neurons at multiple stages of development.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ramamurthy
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: E
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 N Wolfe Street, Baltimore, MD 21205, USA; Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea. Electronic address: gronnett@jhmi.edu.
authors.forename: G V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: 4′,6-diamidino-2-phenylindole; 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside; 5′-adenosine monophosphate-activated protein kinase; ADP; AICAR; AMP; AMPK; ATP; BRSK; BSA; CaMKKβ; DAPI; DIV; DPBS; Dulbecco’s phosphate-buffered saline; GSK-3β; HBSS; HN; Hank’s balanced salt solution; KO; LKB1; MTOR; Map2; P13K; PVDF; RT-PCR; SDS; TBST; Tris-buffered saline+Tween 20; WT; adenosine diphosphate; adenosine monophosphate; adenosine triphosphate; axon; bovine serum albumin; brain-specific kinase; calcium/calmodulin-dependent kinase kinase β; days in vitro; dendrite; development; glycogen synthase kinase 3β; hippocampal neurons; knockout; liver kinase B1; mammalian target of rapamycin; metabolism; microtubule-associated protein 2; neuron; p70 ribosomal protein S6 kinase; p70S6k; phosphatidyl inositol 3-kinase; polyvinylidene difluoride; reverse transcriptase-polymerase chain reaction; sodium dodecyl sulfate; wild type