Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, SE-171 77 Stockholm, Sweden.
Neuropharmacology. 2010 Jun;58(7):1130-9. doi: 10.1016/j.neuropharm.2010.02.005. Epub 2010 Feb 12.
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.
甲状腺激素在早期发育阶段的缺乏会导致大脑在功能和形态上出现多种缺陷。在本研究中，我们研究了突变甲状腺激素受体 TRα1 及其导致的受体介导的甲状腺功能减退症对 GABA 能神经传递和神经元网络癫痫易感性的发展的影响。我们表明，突变小鼠对拮抗 GABA(A)受体复合物引起的癫痫发作具有很强的抵抗力。同样，突变小鼠的海马网络显示出降低的将生理节律性网络活动（如癫痫样发作间期波）转化为病理性节律性网络活动的可能性。正如我们所证明的，这种行为的细胞基础是突变小鼠中 GABA 能神经传递的兴奋性，这可能是由 Cl(-)稳态改变和/或海马门区 calretinin 阳性细胞的异常模式造成的。据我们所知，这项研究首次表明，通过 TRα1，母体和新生儿早期甲状腺功能减退症对 GABA 能神经传递和癫痫易感性的发展有影响。
