Cell type-specific inactivation of Mct8 in brain cells: Gene expression, metabolism, morphology

甲状腺激素（TH）转运蛋白，其中单羧酸转运蛋白8（MCT 8）是必要的适当的大脑发育。MCT 8的突变导致人类严重的精神发育迟滞，即Allan-Herndon-达德利综合征（AHDS）。患者表现为X连锁精神发育迟滞、肌张力减退和血浆TH水平紊乱（高T3，低T4）。已经产生了全局Mct 8缺陷的小鼠模型，并产生了令人惊讶的数据。组织对循环TH水平的反应依赖于转运蛋白的表达，导致肝脏TH过量和伴随的垂体对TH不敏感。类似地，生化和行为数据表明，大脑中甲状腺功能亢进和甲状腺功能减退区域共存。因此，越来越多的证据表明，AHDS患者的神经功能缺损不仅仅是由TH摄取到神经元中的缺陷引起的。为了更好地了解神经和神经生化表型，我们希望考虑到大脑作为一个由神经元、星形胶质细胞、少突胶质细胞和内皮细胞组成的器官的复杂性，因此我们将创建星形胶质细胞和神经元特异性Mct 8敲除小鼠，并重新研究其大脑中的基因表达、能量代谢、TH代谢和树突形态。因此，我们将能够区分由星形胶质细胞或神经元TH不敏感性引起的代谢障碍，从Mct 8缺陷小鼠的血脑屏障缺陷。此外，我们将获得新的见解脑TH代谢的区室化。

Thyroid hormone (TH) transporters and among them monocarboxylate transporter 8 (MCT8) are necessary for proper brain development. Mutations in MCT8 lead to a severe form of psychomotor retardation in humans, the Allan-Herndon-Dudley syndrome (AHDS). Patients present with X-linked mental retardation, muscular hypotonia, and disturbed plasma TH levels (high T3, low T4). Mouse models for global Mct8-deficiency have been generated and yielded surprising data. Tissue responses to circulating TH levels depend on transporter expression leading to hepatic TH excess and concomitant pituitary insensitivity to TH. Similarly, biochemical and behavioural data suggest the coexistence of hyper- and hypothyroid regions in the brain. Thus, evidence is accumulating that the neurological deficits in AHDS patients are not simply caused by defective TH uptake into neurons. In order to better understand the neurological and neurobiochemical phenotypes, we want to take into account the complexity of the brain as an organ composed of neurons, astrocytes, oligodendrocytes, and endothelial cells.We will therefore create astrocyte- and neuron-specific Mct8 knockout mice and re-investigate gene expression, energy metabolism, TH metabolism, and dendritic morphology in their brains. We will thus be able to distinguish metabolic impairments caused by astrocytic or neuronal TH insensitivity from a defective blood-brain-barrier in Mct8-deficient mice. Moreover, we will gain new insight into the compartmentalization of cerebral TH metabolism.