Inhibition of HDAC increases BDNF expression and promotes neuronal rewiring and functional recovery after brain injury

Naoki Sada,Nanano Mizuta,Toshihide Yamashita,Takahisa Furukawa,Yuki Fujita,Masaki Ueno

doi:10.1038/s41419-020-02897-w

Abstract

Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.

Highlights

Traumatic brain injury (TBI) induces severe, longlasting neurological disabilities, including motor, sensory, and cognitive dysfunctions
CI-994, a benzamide-based histone deacetylase (HDAC) inhibitor that is relatively selective for class I HDACs41, was administrated once daily for 14 days via intraperitoneal injection starting at day 28 post-injury
There were no significant differences in corticospinal tract (CST) degeneration between control and HDAC inhibitor-treated mice (Fig. 1b, c)

Summary

Introduction

Traumatic brain injury (TBI) induces severe, longlasting neurological disabilities, including motor, sensory, and cognitive dysfunctions. Studies support the view that partial functional motor recovery can occur spontaneously after focal cerebral cortex injury[1,2,3,4,5,6]. Such recovery is correlated with functional organization of remnant neuronal networks[7,8]. We previously reported that brain-derived neurotrophic factor (BDNF) signaling is required for CST fiber rewiring and behavioral recovery post-injury in mice[11].

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