title: Loss of signal transducer and activator of transcription 3 (STAT3) signaling during elevated activity causes vulnerability in hippocampal neurons.
abstract: Chronically altered levels of network activity lead to changes in the morphology and functions of neurons. However, little is known of how changes in neuronal activity alter the intracellular signaling pathways mediating neuronal survival. Here, we use primary cultures of rat hippocampal neurons to show that elevated neuronal activity impairs phosphorylation of the serine/threonine kinase, Erk1/2, and the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation of serine 727. Chronically stimulated neurons go through apoptosis when they fail to activate another serine/threonine kinase, Akt. Gain- and loss-of-function experiments show that STAT3 plays the key role directly downstream from Erk1/2 as the alternative survival pathway. Elevated neuronal activity resulted in increased expression of a tumor suppressor, p53, and its target gene, Bax. These changes are observed in Kv4.2 knock-out mouse hippocampal neurons, which are also sensitive to the blockade of TrkB signaling, confirming that the alteration occurs in vivo. Thus, this study provides new insight into a mechanism by which chronic elevation of activity may cause neurodegeneration.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. sachikom@ninds.nih.gov
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Kim
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKay
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000473:pathology; D059906:Neuroimaging; D009474:Neurons / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000502:physiology*; D051672:Shal Potassium Channels / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D050796:STAT3 Transcription Factor; D051672:Shal Potassium Channels; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium