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Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure.

Publication ,  Journal Article
Mulholland, PJ; Teppen, TL; Miller, KM; Sexton, HG; Pandey, SC; Swartzwelder, HS
Published in: Alcohol Clin Exp Res
April 2018

BACKGROUND: Adolescent intermittent ethanol (AIE) exposure produces persistent impairments in cholinergic and epigenetic signaling and alters markers of synapses in the hippocampal formation, effects that are thought to drive hippocampal dysfunction in adult rodents. Donepezil (Aricept), a cholinesterase inhibitor, is used clinically to ameliorate memory-related cognitive deficits. Given that donepezil also prevents morphological impairment in preclinical models of neuropsychiatric disorders, we investigated the ability of donepezil to reverse morphological and epigenetic adaptations in the hippocampus of adult rats exposed to AIE. Because of the known relationship between dendritic spine density and morphology with the fragile X mental retardation 1 (Fmr1) gene, we also assessed Fmr1 expression and its epigenetic regulation in hippocampus after AIE and donepezil pretreatment. METHODS: Adolescent rats were administered intermittent ethanol for 16 days starting on postnatal day 30. Rats were treated with donepezil (2.5 mg/kg) once a day for 4 days starting 20 days after the completion of AIE exposure. Brains were dissected out after the fourth donepezil dose, and spine analysis was completed in dentate gyrus granule neurons. A separate cohort of rats, treated identically, was used for molecular studies. RESULTS: AIE exposure significantly reduced dendritic spine density and altered morphological characteristics of subclasses of dendritic spines. AIE exposure also increased mRNA levels and H3-K27 acetylation occupancy of the Fmr1 gene in hippocampus. Treatment of AIE-exposed adult rats with donepezil reversed both the dendritic spine adaptations and epigenetic modifications and expression of Fmr1. CONCLUSIONS: These findings indicate that AIE produces long-lasting decreases in dendritic spine density and changes in Fmr1 gene expression in the hippocampal formation, suggesting morphological and epigenetic mechanisms underlying previously reported behavioral deficits after AIE. The reversal of these effects by subchronic, post-AIE donepezil treatment indicates that these AIE effects can be reversed by up-regulating cholinergic function.

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Published In

Alcohol Clin Exp Res

DOI

EISSN

1530-0277

Publication Date

April 2018

Volume

42

Issue

4

Start / End Page

706 / 717

Location

England

Related Subject Headings

  • Substance Abuse
  • Rats
  • Male
  • Hippocampus
  • Fragile X Mental Retardation Protein
  • Ethanol
  • Epigenesis, Genetic
  • Donepezil
  • Dendritic Spines
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Mulholland, P. J., Teppen, T. L., Miller, K. M., Sexton, H. G., Pandey, S. C., & Swartzwelder, H. S. (2018). Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure. Alcohol Clin Exp Res, 42(4), 706–717. https://doi.org/10.1111/acer.13599
Mulholland, Patrick J., Tara L. Teppen, Kelsey M. Miller, Hannah G. Sexton, Subhash C. Pandey, and H Scott Swartzwelder. “Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure.Alcohol Clin Exp Res 42, no. 4 (April 2018): 706–17. https://doi.org/10.1111/acer.13599.
Mulholland PJ, Teppen TL, Miller KM, Sexton HG, Pandey SC, Swartzwelder HS. Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure. Alcohol Clin Exp Res. 2018 Apr;42(4):706–17.
Mulholland, Patrick J., et al. “Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure.Alcohol Clin Exp Res, vol. 42, no. 4, Apr. 2018, pp. 706–17. Pubmed, doi:10.1111/acer.13599.
Mulholland PJ, Teppen TL, Miller KM, Sexton HG, Pandey SC, Swartzwelder HS. Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure. Alcohol Clin Exp Res. 2018 Apr;42(4):706–717.
Journal cover image

Published In

Alcohol Clin Exp Res

DOI

EISSN

1530-0277

Publication Date

April 2018

Volume

42

Issue

4

Start / End Page

706 / 717

Location

England

Related Subject Headings

  • Substance Abuse
  • Rats
  • Male
  • Hippocampus
  • Fragile X Mental Retardation Protein
  • Ethanol
  • Epigenesis, Genetic
  • Donepezil
  • Dendritic Spines
  • Animals