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 TRα1 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 GABAA 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 TRα1 on the development of GABAergic neurotransmission and susceptibility to epileptic seizures.