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Abstract
Background: Nuclear shuttling of class II histone deacetylases (HDACs) in neurons regulates apoptosis and facilitates neuronal recovery in response to injury. The present study examined the temporal profile of the subcellular localization of class II HDACs (4 and 5) in the peri-infarct cortex during brain recovery after stroke. Methods: Adult male Wistar rats were subjected to permanent middle cerebral artery occlusion (MCAo) and were sacrificed at 2, 7 and 14 days after MCAo. Sham operated rats were used as a control (n=6/group). To identify phenotypes of HDAC immunoreactive cells, double immunohistochemistry was performed with antibodies against each HDAC isoform (4 or 5) along with MAP-2 (a marker of dendrites), p-NFH (a marker of axons), APC (a marker of oligodendrocytes) or GFAP (a marker for astrocytes). Results: In cortical neurons of sham operated rats, HDACs 4 and 5 immunoreactivity was mainly localized to the cytoplasm and dendrites, but not axons. Stroke significantly (p<0.05) increased the percentage of neurons with nuclear HDAC4 immunoreactivity in the peri-infarct cortex at 2 (55 ± 2%), 7 (65 ± 5%) and 14 (76 ± 2%) days after MCAo compared to sham (27 ± 3%). Stroke-induced nuclear expression of HDAC4 was accompanied by a significant (p<0.05) decrease in HDAC4 staining in neuronal dendrites over the same period (7 ± 1% at 2d, 7 ± 2% at 7d, and 6 ± 1% at 14d vs. 19 ± 2% in sham). Neurons with nuclear HDAC4 were not TUNEL positive, indicating that these cells are not apoptotic. In parallel, augmentation of neurons expressing nuclear HDAC4 was significantly correlated to an increase in MAP-2 immunoreactive density after stroke (r=0.7, p<0.05). Stroke-induced nuclear shuttling of HDAC4 is specific to neurons, since HDAC4 was not detected in nuclei of GFAP+ astrocytes or APC+ oligodendrocytes. Neuronal nuclear HDAC4 localization was not associated with a change in Histone H3 lysine 9 acetylation or methylation levels. Unlike HDAC4, stroke did not alter nuclear localization of HDAC5 in neurons. Conclusion: Our data show that stroke induces HDAC4 nuclear shuttling in neurons with increased dendritic density in the peri-infarct cortex, suggesting a role for HDAC4 in promoting neuronal remodeling after stroke.
Published Version
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