Thalamic reticular impairment underlies attention deficit in Ptchd1(Y/-) mice.
Thalamic reticular impairment underlies attention deficit in Ptchd1(Y/-) mice.
复制标题
DOI：
10.1038/nature17427
复制
发表时间：
2016-04-07
期刊：
影响因子：
64.8
通讯作者：
Halassa MM
中科院分区：
文献类型：
--
作者：
Wells MF;Wimmer RD;Schmitt LI;Feng G;Halassa MM
发育障碍，包括注意力缺陷多动障碍(ADHD)、智力障碍(ID)和自闭症谱系障碍(ASD)，在美国每6个儿童中就有1个受到影响。最近，在ID和ASD患者中发现了PTCHD1(Patted-Domaining Protein 1)基因突变。PTCHD1缺失的患者表现出ADHD、睡眠障碍、低眼压、攻击性、ASD和ID的症状。尽管PTCHD1可能对正常发育至关重要，但其缺失与随后的行为缺陷之间的联系尚不清楚。在这里，我们报道了在出生后早期发育过程中，小鼠PTCHD1选择性地表达在丘脑网状核(TRN)，这是一组调节丘脑皮质传递、睡眠节律和注意力的GABA能神经元。PTCHD1缺失通过减少钙依赖性钾电流(SK)来减弱TRN的活性。PTCHD1的TRN限制性缺失导致注意缺陷和多动，这两种情况都可以通过SK通道的药物增强来挽救。整体PTCHD1缺失概括了学习障碍、过度攻击性和运动缺陷，所有这些都对SK药物靶向不敏感，在TRN限制性缺失小鼠中没有发现。这项研究在人类疾病模型中将临床相关的行为表型映射到TRN功能障碍，同时也确定了干预的分子和回路靶点。
Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect 1 in 6 children in the United States. Recently, PTCHD1 (Patched-domain containing protein 1) gene mutations have been found in ~1% of patients with ID and ASD. PTCHD1 deletion patients show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is likely critical for normal development, the connection between its deletion and the ensuing behavioral defects is poorly understood. Here, we report that during early postnatal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamo-cortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity by reducing calcium-dependent potassium currents (SK). Restricted TRN deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channels. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically-relevant behavioral phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.