Abstract
Histone deacetylases (HDACs), HDAC2 in particular, have been shown to regulate various forms of learning and memory. Since cognitive processes share mechanisms with spinal nociceptive signalling, we decided to investigate the HDAC2 expression in the dorsal horn after peripheral injury. Using immunohistochemistry, we found that spinal HDAC2 was mainly seen in neurons and astrocytes, with neuronal expression in naïve tissue 2.6 times greater than that in astrocytes. Cysteine (S)‐nitrosylation of HDAC2 releases HDAC2 gene silencing and is controlled by nitric oxide (NO). A duration of 48 h after intraplantar injection of complete Freund's adjuvant, there was an ipsilateral increase in the most important NO‐producing enzyme in pain states, nitric oxide synthase (nNOS), accompanied by an increase in HDAC2 S‐nitrosylation. Moreover, a subset of nNOS‐positive neurons expressed cFos, a known target of HDAC2, suggesting that derepression of cFos expression following HDAC2 S‐nitrosylation might occur after noxious stimulation. We saw no change in global HDAC2 expression in both short‐ and long‐term pain states. However, HDAC2 was increased in astrocytes 7 days after neuropathic injury suggesting that HDAC2 might inhibit astrocytic gene expression in neuropathic pain states. All together, our results indicate that the epigenetic regulation of transcriptional programmes in the dorsal horn after injury is cell specific. Moreover, the prominent role of NO in persistent pain states suggests that HDAC2 S‐nitrosylation could play a crucial role in the regulation of gene expression leading to hypersensitivity. Our manuscript describes for the first time the regulation of the memory regulator histone deacetylase 2 (HDAC2) in the superficial dorsal horn of adult rats following peripheral injury. Our cell‐specific approach has revealed a complex pattern of expression of spinal HDAC2 that depends on the injury and the cell type, suggesting a sophisticated regulation of gene expression by HDAC2.
Highlights
The modulation of transcriptional programmes is a critical step for the plasticity mechanisms crucial to cognitive processes and for nociceptive signalling (Geranton and Tochiki 2015a,b)
HDAC2 is mainly expressed in neurons and astrocytes in the superficial dorsal horn of na€ıve rats Using immunohistochemistry, we found strong expression of HDAC2 in dorsal horn neurons, labelled with NeuN (Fig. 1a, d1 and d2), and astrocytes, labelled with Gfap (Fig. 1b, d1 (a1) HDAC2 NeuN
We have shown here that HDAC2 activity in the dorsal horn was regulated by S-nitrosylation after injury
Summary
The modulation of transcriptional programmes is a critical step for the plasticity mechanisms crucial to cognitive processes and for nociceptive signalling (Geranton and Tochiki 2015a,b). It is achieved by alterations in chromatin compaction through changes in histone modification at the N-terminal tail and is often accompanied by the recruitment of transcription factors to plasticity-related genes. Histone deacetylases (HDACs) promote chromatin compaction and silencing of gene transcription by removing acetyl groups on histone tails. While synaptic plasticity and memory-inducing paradigms promote histone acetylation in multiple brain regions, HDAC inhibitors improved cognitive performances in animal studies (Penney and Tsai 2014)
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