Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats

Praveen Kumar, Vishwa Mohan, Rohit Anthony Sinha, Megha Chagtoo, Madan M. Godbole

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Thyroid hormone (TH) through its receptor (TRα/β) influences spatio-temporal regulation of its target gene repertoire during brain development. Though hypothyroidism in WT rodent models of perinatal hypothyroidism severely impairs neurodevelopment, its effect on TRα/β knockout mice is less severe. An explanation to this paradox is attributed to a possible repressive action of unliganded TRs during development. Since unliganded TRs suppress gene expression through the recruitment of histone deacetylase (HDACs) via co-repressor complexes, we tested whether pharmacological inhibition of HDACs may prevent the effects of hypothyroidism on brain development. Using valproate, an HDAC inhibitor, we show that HDAC inhibition significantly blocks the deleterious effects of hypothyroidism on rat cerebellum, evident by recovery of TH target genes like Bdnf, Pcp2 and Mbp as well as improved dendritic structure of cerebellar Purkinje neurons. Together with this, HDAC inhibition also rescues hypothyroidism-induced motor and cognitive defects. This study therefore provides an insight into the role of HDACs in TH insufficiency during neurodevelopment and their inhibition as a possible therapeutics for treatment.

Original languageEnglish
Pages (from-to)83-92
Number of pages10
JournalJournal of Endocrinology
Volume227
Issue number2
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Brain development
  • HDACs
  • Hypothyroidism
  • Thyroid hormone receptors

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