Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats.

Daniela Navarro,Manuel Giner,Pere Berbel,Jorge Manzanares,Francisco Navarrete,Mayvi Alvarado,Maria Jesus Obregon

doi:10.3389/fnana.2015.00009

Abstract

Thyroid hormones are fundamental for the expression of genes involved in the development of the CNS and their deficiency is associated with a wide spectrum of neurological diseases including mental retardation, attention deficit-hyperactivity disorder and autism spectrum disorders. We examined in rat whether developmental and early postnatal hypothyroidism affects the distribution of vesicular glutamate transporter-1 (VGluT1; glutamatergic) and vesicular inhibitory amino acid transporter (VGAT; GABAergic) immunoreactive (ir) boutons in the hippocampus and somatosensory cortex, and the behavior of the pups. Hypothyroidism was induced by adding 0.02% methimazole (MMI) and 1% KClO4 to the drinking water starting at embryonic day 10 (E10; developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at postnatal day 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. The distribution, density and size of VGluT1-ir and VGAT-ir boutons in the hippocampus and somatosensory cortex was abnormal in MMI pups and these changes correlate with behavioral changes, as prepulse inhibition of the startle response amplitude was reduced, and the percentage of time spent in open arms increased. In conclusion, both developmental and early postnatal hypothyroidism significantly decreases the ratio of GABAergic to glutamatergic boutons in dentate gyrus leading to an abnormal flow of information to the hippocampus and infragranular layers of the somatosensory cortex, and alter behavior in rats. Our data show cytoarchitectonic alterations in the basic excitatory hippocampal loop, and in local inhibitory circuits of the somatosensory cortex and hippocampus that might contribute to the delayed neurocognitive outcome observed in thyroid hormone deficient children born in iodine deficient areas, or suffering from congenital hypothyroidism.

Highlights

Severe to mild thyroid hormone deficiency during gestation and early postnatal ages causes a wide spectrum of disorders, ranging from stillbirths, miscarriages, congenital anomalies, deafness, neurocognitive delay, and mental retardation (Porterfield and Hendrich, 1993; Hetzel, 1994; Chan and Kilby, 2000; Ahmed et al, 2008; Morreale de Escobar et al, 2008; Berbel and Bernal, 2010; Berbel and Morreale de Escobar, 2011)
Heterotopic neuronal nuclei (NeuN)-ir neurons were observed in the hilus of the dentate gyrus (DG) of MMI pups (Figures 5H,I, arrowheads)
Our data show that in the somatosensory cortex of MMI pups, vesicular glutamate transporter-1 (VGluT1)-ir bouton density is decreased in supra-granular layers, while VGAT-ir bouton densities are decreased compared to controls in all cortical layers except layer I

Summary

Introduction

Severe to mild thyroid hormone deficiency during gestation and early postnatal ages (less than 3 years old) causes a wide spectrum of disorders, ranging from stillbirths, miscarriages, congenital anomalies, deafness, neurocognitive delay, and mental retardation (Porterfield and Hendrich, 1993; Hetzel, 1994; Chan and Kilby, 2000; Ahmed et al, 2008; Morreale de Escobar et al, 2008; Berbel and Bernal, 2010; Berbel and Morreale de Escobar, 2011). In 1990, it was estimated that 1600 million people are exposed to iodine deficiency worldwide (about 25% of the world population of which 11 million suffered from overt cretinism (the most extreme form of mental retardation due to iodine deficiency) and 43 million people were affected by some degree of mental impairment (Glinoer and Delange, 2000). Epidemiological studies have shown low IQ and neurological alterations in children from mildly iodine deficient mothers suffering from hypothyroxinemia, which may affect 25–40% of pregnant women living in mild-moderately iodine deficient countries (Haddow et al, 1999; Pop et al, 2003; Vermiglio et al, 2004; Kasatkina et al, 2006; Kooistra et al, 2006; Berbel et al, 2009; Suárez-Rodríguez et al, 2012; Zimmermann, 2013). Important for the development of cortical connections are genes that code for: Nefh, Nefl and Nefm (neurofilament proteins); Slit, Slit, Nos, BNDF, Camk, and Creb (involved in bifurcation and growth of neural processes); Frontiers in Neuroanatomy www.frontiersin.org Navarroet al.

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