Abstract
Thyroid hormone deficiency during early developmental stages causes a multitude of functional and morphological deficits in the brain. In the present study we investigate the effects of a mutated thyroid hormone receptor TR alpha 1 and the resulting receptor-mediated hypothyroidism on the development of GABAergic neurotransmission and seizure susceptibility of neuronal networks. We show that mutant mice have a strong resistance to seizures induced by antagonizing the GABA(A) receptor complex. Likewise the hippocampal network of mutant mice shows a decreased likelihood to transform physiological into pathological rhythmic network activity such as seizure-like interictal waves. As we demonstrate the cellular basis for this behavior is formed by the excitatory nature of GABAergic neurotransmission in the mutant mice, possibly caused by altered Cl(-) homeostasis, and/or the altered patterning of calretinin-positive cells in the hippocampal hilus. This study is, to our knowledge, the first to show an effect of maternal and early postnatal hypothyroidism via TR alpha 1 on the development of GABAergic neurotransmission and susceptibility to epileptic seizures.
(c) 2010. Published by Elsevier Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / drug effects
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Brain / growth & development
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Brain / physiopathology
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Calbindin 2
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GABA-A Receptor Antagonists
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Hippocampus / drug effects
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Hippocampus / growth & development
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Hippocampus / physiopathology*
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Hypothyroidism / physiopathology*
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K Cl- Cotransporters
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Male
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Mice
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Mice, Transgenic
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Mutation
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Neural Pathways / drug effects
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Neural Pathways / growth & development
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Neural Pathways / physiopathology
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Neurons / drug effects
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Neurons / physiology
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Pyramidal Cells / drug effects
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Pyramidal Cells / growth & development
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Pyramidal Cells / physiopathology
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Receptors, GABA-A / metabolism
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S100 Calcium Binding Protein G / metabolism
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Seizures / chemically induced
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Seizures / physiopathology*
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Sodium-Potassium-Chloride Symporters / metabolism
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Solute Carrier Family 12, Member 2
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Symporters / metabolism
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
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Thyroid Hormone Receptors alpha / genetics
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Thyroid Hormone Receptors alpha / metabolism*
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Thyroid Hormones / metabolism
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Time Factors
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gamma-Aminobutyric Acid / metabolism
Substances
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Calb2 protein, mouse
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Calbindin 2
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GABA-A Receptor Antagonists
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Receptors, GABA-A
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S100 Calcium Binding Protein G
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Slc12a2 protein, mouse
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Sodium-Potassium-Chloride Symporters
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Solute Carrier Family 12, Member 2
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Symporters
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Thyroid Hormone Receptors alpha
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Thyroid Hormones
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gamma-Aminobutyric Acid