BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice
2
조회
0
다운로드
3
인용
0
참고문헌
키워드
초록
Purpose: Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. Methods: To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. Results: We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. Conclusions: Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction.
Abstract
Purpose: Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. Methods: To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. Results: We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. Conclusions: Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction.
참고문헌 (31)
- Barnes JN, "Exercise, cognitive function, and aging", Adv Physiol Educ, 39, pp.55~62 (2015)
- Raftery AE, "Bayesian probabilistic population projections for all countries", Proc Natl Acad Sci U S A, 109, pp.13915~13921 (2012)
- Baker DJ, "BubR1 insufficiency causes early onset of agingassociated phenotypes and infertility in mice", Nat Genet, 36, pp.744~749 (2004)
- Baker DJ, "Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan", Nat Cell Biol, 15, pp.96~102 (2013)
- Bolanos-Garcia VM, "BUB1 and BUBR1: multifaceted kinases of the cell cycle", Trends Biochem Sci, 36, pp.141~150 (2011)
- Hanks S, "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B", Nat Genet, 36, pp.1159~1161 (2004)
- Jacquemont S, "High risk of malignancy in mosaic variegated aneuploidy syndrome", Am J Med Genet, 109, pp.17~21 (2002)
- Lane AH, "Mosaic variegated aneuploidy with growth hormone deficiency and congenital heart defects", Am J Med Genet, 110, pp.273~277 (2002)
- Garcia-Castillo H, "Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes", Am J Med Genet A, 146A, pp.1687~1695 (2008)
- Bohers E, "Gradual reduction of BUBR1 protein levels results in premature sister-chromatid separation then in aneuploidy", Hum Genet, 124, pp.473~478 (2008)
- Suijkerbuijk SJ, "Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy", Cancer Res, 70, pp.4891~4900 (2010)
- Matsuura S, "Monoallelic BUB1B mutations and defective mitoticspindle checkpoint in seven families with premature chromatid separation (PCS) syndrome", Am J Med Genet A, 140, pp.358~367 (2006)
- Warburton D, "Mosaic variegated aneuploidy with microcephaly: a new human mitotic mutant?", Ann Genet, 34, pp.287~292 (1991)
- Miyamoto T, "Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates", Hum Mol Genet, 20, pp.2058~2070 (2011)
- Yang Z, "Agerelated decline in BubR1 impairs adult hippocampal neurogenesis", Aging Cell, 16, pp.598~601 (2017)
- Choi CI, "The progeroid gene BubR1 regulates axon myelination and motor function", Aging (Albany NY), 8, pp.2667~2688 (2016)
- Walf AA, "The use of the elevated plus maze as an assay of anxiety-related behavior in rodents", Nat Protoc, 2, pp.322~328 (2007)
- Jang MH, "Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in mice and humans", Mol Psychiatry, 18, pp.957~958 (2013)
- Hascoet M, "A new approach to the light", dark test procedure in mice, 1998, pp.60, 645~653
- Leger M, "Object recognition test in mice", Nat Protoc, 8, pp.2531~2537 (2013)
- Ge S, "GABA regulates synaptic integration of newly generated neurons in the adult brain", Nature, 439, pp.589~593 (2006)
- Jang MH, "Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis", Cell Stem Cell, 12, pp.215~223 (2013)
- Cohen SJ, "Assessing rodent hippocampal involvement in the novel object recognition task. A review", Behav Brain Res, 285, pp.105~117 (2015)
- Bettio LE, "The effects of aging in the hippocampus and cognitive decline", Neurosci Biobehav Rev, 79, pp.66~86 (2017)
- Ernst A, "Adult neurogenesis in humans- common and unique traits in mammals", PLoS Biology, 13, pp.e1002045~ (2015)
- Fahlström A, "Behavioral changes in aging female C57BL", 6 mice, 2011, pp.32, 1868~1880
- Barreto G, "Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL", 6 mice, 2010, pp.22, 214~219
- Villeda SA, "Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice", Nat Med, 20, pp.659~663 (2014)
- de Fiebre NC, "Spatial learning and psychomotor performance of C57BL", 6 mice: age sensitivity and reliability of individual differences, 2006, pp.28, 235~253
- Guo J, "Developmental disruptions underlying brain abnormalities in ciliopathies", Nat Commun, 6, pp.7857~ (2015)
- Lazarov O, "When neurogenesis encounters aging and disease", Trends Neurosci, 33, pp.569~579 (2010)