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Molecular Neurobiology

, Volume 51, Issue 2, pp 633–647 | Cite as

Vitamin A Deficiency Impairs Spatial Learning and Memory: The Mechanism of Abnormal CBP-Dependent Histone Acetylation Regulated by Retinoic Acid Receptor Alpha

  • Nali Hou
  • Lan Ren
  • Min Gong
  • Yang Bi
  • Yan Gu
  • Zhifang Dong
  • Youxue Liu
  • Jie ChenEmail author
  • Tingyu LiEmail author
Article

Abstract

Vitamin A (VA) is an essential micronutrient. Numerous studies have confirmed that VA deficiency (VAD) leads to a decline in learning and memory function. Our previous studies have demonstrated that retinoic acid nuclear receptor α (RARα) in the hippocampus plays a crucial role in learning and memory, but the exact mechanism for this process is unclear. Epigenetic modifications, particularly histone acetylation, are involved in nervous system development, learning and memory function, and the pathogenesis of neurodegenerative diseases. Histone acetyltransferases (HATs), such as CREB-binding protein (CBP), E1A-binding protein p300 (p300), and p300/CBP-associated factor (PCAF), are critical for regulating memory function. The current study uses RARα and CBP as examples to study the connections between the RA signaling pathway and histone acetylation modification and to reveal the epigenetic mechanism in VAD-induced learning and memory impairment. This study examined the expression of RARα, HATs, acetylated histone H3/H4, and memory-related genes (Zif268, cFos, FosB), as well as the interaction of RARα and CBP in the hippocampus of 8-week-old rats. Additionally, the changes shown in vivo were further assessed in primary cultured neurons with the inhibition or overexpression of RARα. We found significantly lower levels of histone acetylation in the VAD rats. Furthermore, this downregulation, which impairs learning and memory, is induced by the dysregulation of CBP-dependent histone acetylation that is mediated by RARα. This work provides a solid theoretical foundation and experimental basis for the importance of ensuring sufficient nutritional VA during pregnancy and early life to prevent impairments of learning and memory in adulthood.

Keywords

Histone acetylation Vitamin A RARα CBP HATs Learning and memory impairment 

Abbreviations

VA

Vitamin A

VAN

Vitamin A normal

VAD

Vitamin A defiency

RARα

Retinoid acid nuclear receptor α

HATs

Histone acetytransferases

HDACs

Histone deacetylases

HDACis

Histone deacetylase inhibitors

RARE

Retinoic acid response element

NSE

Neuron-specific enolase

DG

Dentate gyrus

CBP

CREB-binding protein

p300

E1A-binding protein

PCAF

p300/CBP-associated factor

ChIP

Chromatin immunoprecipitation

Notes

Acknowledgements

This work was supported by the Specialized Research Fund for the National Natural Science Foundation of China (No. 81161120498, 81271221) and the Research Fund for the Doctoral Program of Higher Education of China (No. 20115503110003).

Conflict of Interest

The authors declare no competing financial interests.

Author Contributions

Nali Hou, Min Gong, Yang Bi, Zhifang Dong, Jie Chen, and Tingyu Li designed the research. Nali Hou performed experiments. Lan Ren and Yan Gu helped Nali Hou in experiments. Nali Hou, Min Gong, Jie Chen, and Youxue Liu analyzed the data. Nali Hou, Min Gong, Jie Chen, and Tingyu Li wrote the paper. All authors read and approved the final manuscript.

Supplementary material

12035_2014_8741_Fig8_ESM.gif (23 kb)
Fig. S1

Quantification of fluorescence intensity for the colocalization of RARα and CBP in the rat hippocampus (CA1, CA3, DG). The coexpression of RARα and CBP was weaker in the CA1, CA3 and DG region of the hippocampus in VAD than that in VAN, respectively. The reported values are shown as the mean ± SEM, and the above data were confirmed in at least six samples for each region and each sample was tested in triplicate (n = 6, ***p<0.001). (GIF 23 kb)

12035_2014_8741_MOESM1_ESM.tif (3.1 mb)
High Resolution Image (TIFF 3179 kb)
12035_2014_8741_Fig9_ESM.gif (261 kb)
Fig. S2

Identification and infection of the primary cultured neurons. a Immunofluorescence staining of neuronal marker NSE in neurons was used to identify the primary cultured cells, and the purity of greater than 90 % was achieved. TD bright light, green expression of NSE, blue DAPI, multicolor merged images of TD, NSE and DAPI. b TD neurons before adenovirus infection, growing well. Primary neurons on day 6 after infection with RFP, siRARα or Ad-RARα, respectively, were positive for RFP under the fluorescence microscope and had similar infection levels. c Primary neurons on day 6 after co-infection with Ad-RARα and siCBP or the negative control GFP lentivirus (NC) were positive for GFP and RFP, respectively, under the fluorescence microscope and showed similar infection levels. Green expression of NC or siCBP, red Ad-RARα, multicolor merged images of TD, Ad-RARRα and siCBP or NC. The original magnification is 200×; scale bars are 20 μm. (GIF 260 kb)

12035_2014_8741_MOESM2_ESM.tif (9.6 mb)
High Resolution Image (TIFF 9819 kb)
12035_2014_8741_Fig10_ESM.gif (30 kb)
Fig. S3

Inhibition of CBP did not affect the expression levels of RARα. a CBP mRNA expression was reduced significantly after infection with siCBP lentivirus (n = 6, *p < 0.05). b RARα mRNA was not obviously affected after treatment with siCBP (n = 6, ns, nonsignificant). c The expression of RARα protein levels showed no significant changes after inhibition of CBP. The results were normalized against LaminB. (GIF 30 kb)

12035_2014_8741_MOESM3_ESM.tif (7.6 mb)
High Resolution Image (TIFF 7745 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nali Hou
    • 1
    • 2
  • Lan Ren
    • 1
    • 2
  • Min Gong
    • 1
    • 2
  • Yang Bi
    • 1
    • 2
  • Yan Gu
    • 1
    • 2
  • Zhifang Dong
    • 1
    • 2
  • Youxue Liu
    • 1
    • 2
  • Jie Chen
    • 1
    • 2
    Email author
  • Tingyu Li
    • 1
    • 2
    Email author
  1. 1.Children Nutrition Research CenterChildren’s Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Ministry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChongqingChina

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