Gilbert M E, Paczkowski C
Neurotoxicology Division (MD-B105-05), National Health and Environmental Effects Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Brain Res Dev Brain Res. 2003 Oct 10;145(1):19-29. doi: 10.1016/s0165-3806(03)00191-3.
Reductions in thyroid hormone during critical periods of brain development can have devastating effects on neurological function that are permanent. Neurochemical, molecular and structural alterations in a variety of brain regions have been well documented, but little information is available on the consequences of developmental hypothyroidism on synaptic function. Developing rats were exposed to the thyrotoxicant, propylthiouracil (PTU: 0 or 15 ppm), through the drinking water of pregnant dams beginning on GD18 and extending throughout the lactational period. Male offspring were allowed to mature after termination of PTU exposure at weaning on PND21 and electrophyiological assessments of field potentials in the dentate gyrus were conducted under urethane anesthesia between 2 and 5 months of age. PTU dramatically reduced thyroid hormones on PND21 and produced deficits in body weight that persisted to adulthood. Synaptic transmission was impaired as evidenced by reductions in excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitudes at a range of stimulus intensities. Long-term potentiation of the EPSP slope was impaired at both modest and strong intensity trains, whereas a paradoxical increase in PS amplitude was observed in PTU-treated animals in response to high intensity trains. These data are the first to describe functional impairments in synaptic transmission and plasticity in situ as a result of PTU treatment and suggest that perturbations in synaptic function may contribute to learning deficits associated with developmental hypothyroidism.
在大脑发育的关键时期甲状腺激素减少会对神经功能产生永久性的毁灭性影响。多种脑区的神经化学、分子和结构改变已有充分记录，但关于发育性甲状腺功能减退对突触功能的影响却知之甚少。从妊娠第18天开始，通过给怀孕母鼠饮用的水使其接触甲状腺毒剂丙硫氧嘧啶（PTU：0或15 ppm），并持续整个哺乳期。雄性后代在出生后第21天断奶时停止接触PTU后使其成熟，并在2至5月龄时在乌拉坦麻醉下对齿状回的场电位进行电生理评估。PTU在出生后第21天显著降低了甲状腺激素，并导致体重缺陷持续至成年期。兴奋性突触后电位（EPSP）斜率和群体峰电位（PS）幅度在一系列刺激强度下均降低，这表明突触传递受损。在适度和强烈强度的刺激串下，EPSP斜率的长时程增强均受损，而在PTU处理的动物中，对高强度刺激串的反应观察到PS幅度出现反常增加。这些数据首次描述了PTU处理导致的原位突触传递和可塑性的功能损害，并表明突触功能的紊乱可能导致与发育性甲状腺功能减退相关的学习缺陷。
