HDAC3-mediated repression of the Nr4a family contributes to age-related impairments in long-term memory

Janine L. Kwapis, Yasaman Alaghband, Alberto J. López, Jeffrey M. Long, Xiang Li, Guanhua Shu, Kasuni K. Bodinayake, Dina P. Matheos, Peter R. Rapp, Marcelo A. Wood

Research output: Contribution to journalArticle

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Abstract

Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is the Nr4a family of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role of Nr4a1 and Nr4a2 in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified Nr4a2 as a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulates Nr4a2 in the aged male and female hippocampus. Finally, we show that overexpression of Nr4a1, Nr4a2, or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that Nr4a2 may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of Nr4a2 contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote Nr4a gene expression or function may be an effective strategy to improve cognitive function in old age.

Original languageEnglish (US)
Pages (from-to)4999-5009
Number of pages11
JournalJournal of Neuroscience
Volume39
Issue number25
DOIs
StatePublished - Jun 19 2019

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Long-Term Memory
Cognition
Hippocampus
Orphan Nuclear Receptors
Genetic Models
Individuality
Genes
histone deacetylase 3
Learning
Gene Expression
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Kwapis, Janine L. ; Alaghband, Yasaman ; López, Alberto J. ; Long, Jeffrey M. ; Li, Xiang ; Shu, Guanhua ; Bodinayake, Kasuni K. ; Matheos, Dina P. ; Rapp, Peter R. ; Wood, Marcelo A. / HDAC3-mediated repression of the Nr4a family contributes to age-related impairments in long-term memory. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 25. pp. 4999-5009.
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abstract = "Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is the Nr4a family of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role of Nr4a1 and Nr4a2 in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified Nr4a2 as a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulates Nr4a2 in the aged male and female hippocampus. Finally, we show that overexpression of Nr4a1, Nr4a2, or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that Nr4a2 may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of Nr4a2 contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote Nr4a gene expression or function may be an effective strategy to improve cognitive function in old age.",
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Kwapis, JL, Alaghband, Y, López, AJ, Long, JM, Li, X, Shu, G, Bodinayake, KK, Matheos, DP, Rapp, PR & Wood, MA 2019, 'HDAC3-mediated repression of the Nr4a family contributes to age-related impairments in long-term memory', Journal of Neuroscience, vol. 39, no. 25, pp. 4999-5009. https://doi.org/10.1523/JNEUROSCI.2799-18.2019

HDAC3-mediated repression of the Nr4a family contributes to age-related impairments in long-term memory. / Kwapis, Janine L.; Alaghband, Yasaman; López, Alberto J.; Long, Jeffrey M.; Li, Xiang; Shu, Guanhua; Bodinayake, Kasuni K.; Matheos, Dina P.; Rapp, Peter R.; Wood, Marcelo A.

In: Journal of Neuroscience, Vol. 39, No. 25, 19.06.2019, p. 4999-5009.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HDAC3-mediated repression of the Nr4a family contributes to age-related impairments in long-term memory

AU - Kwapis, Janine L.

AU - Alaghband, Yasaman

AU - López, Alberto J.

AU - Long, Jeffrey M.

AU - Li, Xiang

AU - Shu, Guanhua

AU - Bodinayake, Kasuni K.

AU - Matheos, Dina P.

AU - Rapp, Peter R.

AU - Wood, Marcelo A.

PY - 2019/6/19

Y1 - 2019/6/19

N2 - Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is the Nr4a family of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role of Nr4a1 and Nr4a2 in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified Nr4a2 as a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulates Nr4a2 in the aged male and female hippocampus. Finally, we show that overexpression of Nr4a1, Nr4a2, or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that Nr4a2 may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of Nr4a2 contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote Nr4a gene expression or function may be an effective strategy to improve cognitive function in old age.

AB - Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is the Nr4a family of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role of Nr4a1 and Nr4a2 in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified Nr4a2 as a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulates Nr4a2 in the aged male and female hippocampus. Finally, we show that overexpression of Nr4a1, Nr4a2, or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that Nr4a2 may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of Nr4a2 contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote Nr4a gene expression or function may be an effective strategy to improve cognitive function in old age.

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