Background
Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses.
Methods
To identify the METH-induced epigenetic underpinnings of these neuroadaptations, we
injected increasing METH doses to rats for 2 weeks and measured striatal glutamate
receptor expression. We then quantified the effects of METH exposure on histone acetylation.
We also measured METH-induced changes in DNA methylation and DNA hydroxymethylation.
Results
Chronic METH decreased transcript and protein expression of GluA1 and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid receptor (AMPAR) and GluN1 N-methyl-D-aspartate receptor subunits. These changes were associated with altered
electrophysiological glutamatergic responses in striatal neurons. Chromatin immunoprecipitation-polymerase
chain reaction revealed that METH decreased enrichment of acetylated histone H4 on
GluA1, GluA2, and GluN1 promoters. Methamphetamine exposure also increased repressor
element-1 silencing transcription factor (REST) corepressor 1, methylated CpG binding
protein 2, and histone deacetylase 2 enrichment, but not of sirtuin 1 or sirtuin 2,
onto GluA1 and GluA2 gene sequences. Moreover, METH caused interactions of REST corepressor
1 and methylated CpG binding protein 2 with histone deacetylase 2 and of REST with
histone deacetylase 1. Surprisingly, methylated DNA immunoprecipitation and hydroxymethylated
DNA immunoprecipitation-polymerase chain reaction revealed METH-induced decreased
enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter
sequences. Importantly, the histone deacetylase inhibitor, valproic acid, blocked
METH-induced decreased expression of AMPAR and N-methyl-D-aspartate receptor subunits. Finally, valproic acid also attenuated METH-induced
decrease H4K16Ac recruitment on AMPAR gene sequences.
Conclusions
These observations suggest that histone H4 hypoacetylation may be the main determinant
of METH-induced decreased striatal glutamate receptor expression.
Key Words
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Article info
Publication history
Published online: November 18, 2013
Accepted:
September 30,
2013
Received in revised form:
September 27,
2013
Received:
January 29,
2013
Identification
Copyright
Published by Elsevier Inc.
