Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for histone deacetylase 4.
Neuronal gene expression is modulated by activity via calcium-permeable receptors such as NMDA receptors (NMDARs). While gene expression changes downstream of evoked NMDAR activity have been well studied, much less is known about gene expression changes that occur under conditions of basal neuronal activity. In mouse dissociated hippocampal neuronal cultures, we found that a broad NMDAR antagonist, AP5, induced robust gene expression changes under basal activity, but subtype-specific antagonists did not. While some of the gene expression changes are also known to be downstream of stimulated NMDAR activity, others appear specific to basal NMDAR activity. The genes altered by AP5 treatment of basal cultures were enriched for pathways related to class IIa histone deacetylases (HDACs), apoptosis, and synapse-related signaling. Specifically, AP5 altered the expression of all three class IIa HDACs that are highly expressed in the brain, HDAC4, HDAC5, and HDAC9, and also induced nuclear accumulation of HDAC4. HDAC4 knockdown abolished a subset of the gene expression changes induced by AP5, and led to neuronal death under long-term tetrodotoxin or AP5 treatment in rat hippocampal organotypic slice cultures. These data suggest that basal, but not evoked, NMDAR activity regulates gene expression in part through HDAC4, and, that HDAC4 has neuroprotective functions under conditions of low NMDAR activity.
Departments of Neuroscience.
Yelin
Y
Chen
Departments of Neuroscience.
Yuanyuan
Y
Wang
Molecular Biology, Genentech Inc., South San Francisco, California 94080.
Zora
Z
Modrusan
Departments of Neuroscience, sheng.morgan@gene.com kaminker.josh@gene.com.
Morgan
M
Sheng
Departments of Neuroscience, Bioinformatics and Computational Biology, and sheng.morgan@gene.com kaminker.josh@gene.com.
Joshua S
JS
Kaminker
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000633:toxicity; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D013779:Tetrodotoxin; C056639:2-amino-5-phosphopentanoic acid; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D014633:Valine
HDAC4; NMDA receptor; activity-dependent gene expression; apoptosis