title: Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats.
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.
authors.affiliation: Department of Molecular Medicine and BiotechnologySanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, IndiaDepartment of Biochemistry and BiophysicsUNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USACardiovascular and Metabolic Disorder ProgramLaboratory of Hormonal Regulation, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Molecular Medicine and BiotechnologySanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, IndiaDepartment of Biochemistry and BiophysicsUNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USACardiovascular and Metabolic Disorder ProgramLaboratory of Hormonal Regulation, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Vishwa
authors.initials: V
authors.lastname: Mohan
authors.affiliation: Department of Molecular Medicine and BiotechnologySanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, IndiaDepartment of Biochemistry and BiophysicsUNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USACardiovascular and Metabolic Disorder ProgramLaboratory of Hormonal Regulation, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore rohit.sinha@duke-nus.edu.sg madangodbole@yahoo.co.in.
authors.forename: Rohit Anthony
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: Department of Molecular Medicine and BiotechnologySanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, IndiaDepartment of Biochemistry and BiophysicsUNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USACardiovascular and Metabolic Disorder ProgramLaboratory of Hormonal Regulation, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Megha
authors.initials: M
authors.lastname: Chagtoo
authors.affiliation: Department of Molecular Medicine and BiotechnologySanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, IndiaDepartment of Biochemistry and BiophysicsUNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USACardiovascular and Metabolic Disorder ProgramLaboratory of Hormonal Regulation, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore rohit.sinha@duke-nus.edu.sg madangodbole@yahoo.co.in.
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities* / Q000187:drug effects* / Q000201:enzymology; D056970:Co-Repressor Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000378:metabolism; D007037:Hypothyroidism / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy*; D008713:Methimazole / Q000494:pharmacology; D065886:Neurodevelopmental Disorders / Q000209:etiology / Q000517:prevention & control*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013963:Thyroid Hormones / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D056970:Co-Repressor Proteins; D056572:Histone Deacetylase Inhibitors; D013963:Thyroid Hormones; D008713:Methimazole; D014635:Valproic Acid; D006655:Histone Deacetylases
keywords: HDACs; brain development; hypothyroidism; thyroid hormone receptors