A mutant thyroid hormone receptor alpha1 alters hippocampal circuitry and reduces seizure susceptibility in mice.
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.
Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, SE-171 77 Stockholm, Sweden.
Saïda
S
Hadjab-Lallemend
Karin
K
Wallis
Max
M
van Hogerlinden
Susi
S
Dudazy
Kristina
K
Nordström
Björn
B
Vennström
André
A
Fisahn
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D064032:Calbindin 2; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology*; D007037:Hypothyroidism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009434:Neural Pathways / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096922:K Cl- Cotransporters
D064032:Calbindin 2; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D064030:S100 Calcium Binding Protein G; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C576511:Calb2 protein, mouse; C578878:Slc12a2 protein, mouse