Citation

Sagarkar S, Balasubramanian N, Mishra S, Choudhary AG, Kokare DM, Sakharkar AJ. Brain Res. 2019; 1711: 183-192.

Affiliation

Department of Biotechnology, Savitribai Phule Pune University, Pune 411 007, India. Electronic address: amul.sakharkar@unipune.ac.in.

Copyright

(Copyright © 2019, International Brain Research Organization, Publisher Elsevier Publishing)

DOI

10.1016/j.brainres.2019.01.022

PMID

30664848

Abstract

Impaired attention and memory represent some of the major long-term consequences of brain injuries. However, little is known about the underlying molecular mechanisms of brain trauma-induced cognitive decline. Histone deacetylases (HDACs) in the hippocampus are believed to impact learning and memory. Herein, we have induced repeated mild traumatic brain injury (rMTBI) in rats by using weight-drop paradigm, examined the recognition memory using novel object recognition task, and assessed the HDAC activities in the hippocampus post 48 hrs and 30 days of rMTBI. The recognition memory was significantly compromised in the rMTBI-exposed rats at both the time points. The rMTBI also increased mRNA levels of different isoforms of HDACs (HDAC2-5 and HDAC11) at different time points coupled with rise in nuclear and cytosolic HDAC activities. However, a mild decrease in HDAC8 mRNA levels was also observed at 30 days time point. As a corollary, rMTBI also caused persistent decrease in the levels of acetylated histone H3-Lys 9 (H3-K9ac) in promoter region of cocaine- and amphetamine-regulated transcript (CART) gene with concurrent decline in CART mRNA and peptide (CARTp) levels. Furthermore, the treatment with trichostatin A (TSA), a pan HDAC inhibitor, restored the rMTBI-induced deficits in recognition memory and HDAC activities with commensurate changes in the H3-K9ac and CART mRNA levels. Together, these results suggest that rMTBI may trigger persistent changes in HDAC-mediated histone acetylation at the CART gene promoter culminating into deficits in learning and memory. Further, the present study also identifies therapeutic potential of HDAC inhibitors in rescuing MTBI-induced cognitive deficits.

Copyright © 2019. Published by Elsevier B.V.

Language: en

Keywords

Cocaine- and amphetamine-regulated transcript peptide; HDAC inhibitors; Hippocampus; Learning and memory; Mild traumatic brain injury