Abstract
In neurons, dynamic changes in the subcellular localization of histone deacetylases (HDACs) are thought to contribute to signal-regulated gene expression. Here we show that in mouse hippocampal neurons, synaptic activity-dependent nucleo-cytoplasmic shuttling is a common feature of all members of class IIa HDACs, which distinguishes them from other classes of HDACs. Nuclear calcium, a key regulator in neuronal gene expression, is required for the nuclear export of a subset of class IIa HDACs. We found that inhibition of nuclear calcium signaling using CaMBP4 or increasing the nuclear calcium buffering capacity by means of expression of a nuclear targeted version of parvalbumin (PV.NLS-mC) led to a build-up of HDAC4 and HDAC5 in the cell nucleus, which in the case of PV.NLS-mC can be reversed by nuclear calcium transients triggered by bursts of action potential firing. A similar nuclear accumulation of HDAC4 and HDAC5 was observed in vivo in the mouse hippocampus following stereotaxic delivery of recombinant adeno-associated viruses expressing either CaMBP4 or PV.NLS-mC. The modulation of HDAC4 activity either by RNA interference-mediated reduction of HDAC4 protein levels or by expression of a constitutively nuclear localized mutant of HDAC4 leads to changes in the mRNA levels of several nuclear calcium-regulated genes with known functions in acquired neuroprotection (atf3, serpinb2), memory consolidation (homer1, arc), and the development of chronic pain (ptgs2, c1qc). These results identify nuclear calcium as a regulator of nuclear export of HDAC4 and HDAC5. The reduction of nuclear localized HDACs represents a novel transcription-promoting pathway stimulated by nuclear calcium.
Highlights
Class IIa histone deacetylases (HDACs) shuttle in a signal-regulated manner between the nucleus and cytosol
The subcellular localization of HDAC3 and HDAC11 was largely invariant with the treatments indicating that HDAC classical HDAC family (class I) and IV subcellular distribution is not regulated by neuronal activity (Fig. 1A)
We investigated the role of nuclear calcium signaling on HDAC shuttling in vivo. Recombinant Adeno-associated Viruses (rAAVs) containing the expression cassettes for mCherry-nuclear localization signal (NLS), CaMBP4-mCherry, or PV.NLS-mC were stereotaxically delivered into the ventral mouse hippocampus of 2-month-old C57BL/6 male mice; infected neurons could readily be identified by mCherry fluorescence (Fig. 6)
Summary
Class IIa HDACs shuttle in a signal-regulated manner between the nucleus and cytosol. The modulation of HDAC4 activity either by RNA interferencemediated reduction of HDAC4 protein levels or by expression of a constitutively nuclear localized mutant of HDAC4 leads to changes in the mRNA levels of several nuclear calcium-regulated genes with known functions in acquired neuroprotection (atf, serpinb2), memory consolidation (homer, arc), and the development of chronic pain (ptgs, c1qc) These results identify nuclear calcium as a regulator of nuclear export of HDAC4 and HDAC5. In addition to causing increases in histone acetylation and DNA methylation (11, 14 –19), the stimulation of HDAC nuclear export by nuclear calcium represents an additional pathway that links synaptic activity to genome-wide changes in chromatin structure facilitating gene transcription
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