Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons

Ernest Palomer, Adrián Martín-Segura, Shishir Baliyan, Tariq Ahmed, Detlef Balschun, Cesar Venero, Mauricio G. Martin, Carlos G. Dotti

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.

Original languageEnglish
Pages (from-to)2889-2900
Number of pages12
JournalCell Reports
Volume16
Issue number11
DOIs
Publication statusPublished - 13 Sep 2016
Externally publishedYes

Fingerprint

Neurons
Chromatin
Aging of materials
Cholesterol
Calcium-Calmodulin-Dependent Protein Kinase Type 2
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Chemical activation
Histone Acetyltransferases
Acetylation
Neuronal Plasticity
Histone Deacetylases
Chromatin Assembly and Disassembly
Transcription
Plasticity
Genes
Pharmacology
Defects
Cognitive Dysfunction
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Palomer, E., Martín-Segura, A., Baliyan, S., Ahmed, T., Balschun, D., Venero, C., ... Dotti, C. G. (2016). Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons. Cell Reports, 16(11), 2889-2900. https://doi.org/10.1016/j.celrep.2016.08.028

Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons. / Palomer, Ernest; Martín-Segura, Adrián; Baliyan, Shishir; Ahmed, Tariq; Balschun, Detlef; Venero, Cesar; Martin, Mauricio G.; Dotti, Carlos G.

In: Cell Reports, Vol. 16, No. 11, 13.09.2016, p. 2889-2900.

Research output: Contribution to journalArticle

Palomer, E, Martín-Segura, A, Baliyan, S, Ahmed, T, Balschun, D, Venero, C, Martin, MG & Dotti, CG 2016, 'Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons', Cell Reports, vol. 16, no. 11, pp. 2889-2900. https://doi.org/10.1016/j.celrep.2016.08.028
Palomer E, Martín-Segura A, Baliyan S, Ahmed T, Balschun D, Venero C et al. Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons. Cell Reports. 2016 Sep 13;16(11):2889-2900. https://doi.org/10.1016/j.celrep.2016.08.028
Palomer, Ernest ; Martín-Segura, Adrián ; Baliyan, Shishir ; Ahmed, Tariq ; Balschun, Detlef ; Venero, Cesar ; Martin, Mauricio G. ; Dotti, Carlos G. / Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons. In: Cell Reports. 2016 ; Vol. 16, No. 11. pp. 2889-2900.
@article{90c395910c904c2f8d17efc2fb4812a2,
title = "Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons",
abstract = "Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.",
author = "Ernest Palomer and Adri{\'a}n Mart{\'i}n-Segura and Shishir Baliyan and Tariq Ahmed and Detlef Balschun and Cesar Venero and Martin, {Mauricio G.} and Dotti, {Carlos G.}",
year = "2016",
month = "9",
day = "13",
doi = "10.1016/j.celrep.2016.08.028",
language = "English",
volume = "16",
pages = "2889--2900",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",

}

TY - JOUR

T1 - Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons

AU - Palomer, Ernest

AU - Martín-Segura, Adrián

AU - Baliyan, Shishir

AU - Ahmed, Tariq

AU - Balschun, Detlef

AU - Venero, Cesar

AU - Martin, Mauricio G.

AU - Dotti, Carlos G.

PY - 2016/9/13

Y1 - 2016/9/13

N2 - Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.

AB - Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.

UR - http://www.scopus.com/inward/record.url?scp=84991625004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991625004&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.08.028

DO - 10.1016/j.celrep.2016.08.028

M3 - Article

VL - 16

SP - 2889

EP - 2900

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -