Methamphetamine Downregulates Striatal Glutamate Receptors via Diverse Epigenetic Mechanisms

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• 作者：Subramaniam Jayanthi^a ; Michael T. McCoy^a ; Billy Chen^b ; Jonathan P. Britt^b ; Sa褩d Kourrich^b ; Hau-Jie Yau^b ; Bruce Ladenheim^a ; Irina N. Krasnova^a ; Antonello Bonci^b ; Jean Lud Cadet^a ; ^{jcadet@intra.nida.nih.gov" class="auth_mail}
• 关键词：Addiction ; AMPAR ; CoREST ; HDAC2 ; MeCP2 ; NMDAR ; REST ; valproic acid
• 刊名：Biological Psychiatry
• 出版年：1 July 2014
• 年：2014
• 卷：76
• 期：1
• 页码：47-56
• 全文大小：692 K

文摘

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.