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Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure
Author(s) -
Mulholland Patrick J.,
Teppen Tara L.,
Miller Kelsey M.,
Sexton Hannah G.,
Pandey Subhash C.,
Swartzwelder H. Scott
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13599
Subject(s) - dendritic spine , donepezil , hippocampus , epigenetics , neuroscience , fmr1 , brain morphometry , spine (molecular biology) , medicine , hippocampal formation , biology , dementia , microbiology and biotechnology , genetics , disease , fragile x , gene , radiology , magnetic resonance imaging
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.