Intracellular Trafficking of Histone Deacetylase 4 Regulates Long‐Term Memory Formation

Abstract

Histone acetylation is important for gene transcription, which is controlled by the balance between two kinds of opposing enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDACs repress gene transcription by decreasing histone acetylation levels. Our hypothesis was that shuttling of Class II HDACs, such as HDAC4, between the nucleus and cytoplasm is critical for its function. We constructed mutants of mammalian HDAC4 that had different cellular locations and checked their function during memory formation using Caenorhabditis elegans as a model. The deletion of hda4, a homolog of HDAC4, was able to enhance learning and long-term memory (LTM) in a thermotaxis model. Transgenic experiments showed that mammalian wild-type HDAC4 rescued the phenotype of hda4-deleted worms but impaired LTM formation in wild-type worms. The cytosol-localized HDAC4 mutant was not able to alter the phenotype of knock-out worms but led to enhanced LTM formation in wild-type worms similar to hda4-deletion mutants. Constitutive nuclear localization of HDAC4 rescued the phenotype of deletion worms similar to wild-type HDAC4 but had no effect on wild-type worms. These results support our hypothesis that HDAC4's biological function is regulated by its intracellular distribution. Anat Rec, 294:1025Rec, 294: -1034Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

“…restored memory to wild-type levels), thus acting as a memory repressor. Expression of a cytoplasmically-restricted mutant (DN118 which lacks the NLS) had no effect on the memory of hda-4 worms, indicating that nuclear activity represses memory, which is consistent with data from other model systems (Wang et al, 2011). The subcellular localization of endogenous Hda-4 was not examined, but this would be an informative analysis because if it is strongly nuclear, it would explain how loss of Hda-4 improves memory and why it contrasts with data from other model systems.…”

“…In contrast to the memory deficits observed in other model organisms, worms harboring an hda-4 deletion allele displayed enhanced performance when tested in a model of thermosensation memory (Wang et al, 2011). Expression of wild-type or the nuclear-restricted 3SA mutant of human HDAC4 abolished the enhanced memory phenotype (e.g.…”

Targeting Histone Deacetylases in Diseases: Where Are We?

“…HDAC1, 2, 3, and 8 belong to class I and are localized in the nucleus, presenting similarity to the yeast Rpd3 (47). Class II HDACs (229) are present in both the cytoplasm and nucleus, and they shuttle between these compartments (113,147,234). Class II HDACs (grouped for homology to Hda1 in yeast) are divided into two subclasses: class IIa (HDAC4, 5, 7, and 9) and class IIb (HDAC6, 10).…”

Histone Deacetylase Inhibitors and Psychiatric Disorders

“…Wang et al [38] Loss of HDAC4 impairs LTP and associative and spatial memories. HDAC4 regulates neuronal plasticity linked to addiction.…”

“…Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, developmental delays, and behavioral problems. Brain-specific deletion of HDAC4 impairs long-term potentiation Liu et al [51] (Continued) (LTP) and memory in mice and nematodes [38,39]. It also has been shown to play a role in inhibiting cell-cycle progression and in preventing neuronal cell apoptosis.…”