期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 99, 期 26, 页码 17095-17100出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.262658999
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资金
- NIMH NIH HHS [MH62682-01, R01 MH062188, MH062090, R01 MH062682, MH062188, R01 MH062090] Funding Source: Medline
Reelin and glutamic acid decarboxylase (GAD)(67) expressed by cortical gamma-aminobutyric acid-ergic interneurons are downregulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this downregulation. Protracted L-methionine (6.6 mmol/kg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-meth ion i ne, and a marked decrease of reelin and GAD(67) mRNAs in both WT and heterozygous ree/er mice. This effect of L-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD(65) or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of L-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulse/startle interval increased in mice receiving L-methionine. Valproic acid (2 mmol/kg for 15 days, twice a day) reverted L-methionine-induced down-regulation of reelin and GAD(67) in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk.
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