title: Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning.
abstract: A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38αAF/+and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD.
authors.affiliation: Department of Neurology, University of Texas Medical Branch at Galveston, Galveston TX, USA; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch at Galveston, Galveston TX, USA; Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston TX, USA. Electronic address: ibcortez@utmb.edu.
authors.forename: IbDanelo
authors.initials: I
authors.lastname: Cortez
authors.affiliation: Institute for Research on Cancer and Ageing of Nice, INSERM, University of Nice, France.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bulavin
authors.affiliation: Department of Neuroscience & Cell Biology, University of Texas Medical Branch at Galveston, Galveston TX, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Neuroscience & Cell Biology, University of Texas Medical Branch at Galveston, Galveston TX, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: McGrath
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, Galveston TX, USA; Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston TX, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Cunningham
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston TX, USA; Transgenic Mouse Core Facility, University of Texas Medical Branch at Galveston, Galveston TX, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
authors.affiliation: Department of Neurology, University of Texas Medical Branch at Galveston, Galveston TX, USA; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch at Galveston, Galveston TX, USA; Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston TX, USA.
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000201:enzymology / Q000473:pathology; D003213:Conditioning, Psychological / Q000502:physiology; D004192:Discrimination, Psychological / Q000502:physiology*; D004597:Electroshock; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology* / Q000523:psychology; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency* / Q000235:genetics; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D011581:Psychological Tests
chemical_list: D048308:Mitogen-Activated Protein Kinase 14
keywords: Adult neurogenesis; Aging; Behavior; Context discrimination; Fear conditioning; Hippocampus