Jang Sung-Soo, Takahashi Fuga, Huguenard John R
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Adv. 2025 Aug 22;11(34):eadw4682. doi: 10.1126/sciadv.adw4682. Epub 2025 Aug 20.
Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by social deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Although thalamocortical circuit dysfunction has been implicated in these symptoms, its precise roles in ASD pathophysiology remain poorly understood. Here, we examine the specific contribution of the reticular thalamic nucleus (RT), a key modulator of thalamocortical activity, to ASD-related behavioral deficits using a knockout mouse model. mice displayed increased seizure susceptibility, locomotor activity, and repetitive behaviors. Electrophysiological recordings revealed enhanced intrathalamic oscillations and burst firing in RT neurons, accompanied by elevated T-type calcium currents. In vivo fiber photometry confirmed behavior-associated increases in RT population activity. Notably, pharmacological and chemogenetic suppression of RT excitability via Z944, a T-type calcium channel blocker, and via C21 activation of the inhibitory DREADD hM4Di significantly improved ASD-related behaviors. These findings identify RT hyperexcitability as a mechanistic driver of ASD and highlight RT as a potential therapeutic target.
自闭症谱系障碍（ASD）是一种神经发育疾病，其特征为社交缺陷、重复行为以及共病情况，如感觉异常、睡眠障碍和癫痫发作。尽管丘脑皮质回路功能障碍与这些症状有关，但其在ASD病理生理学中的具体作用仍知之甚少。在这里，我们使用基因敲除小鼠模型研究丘脑网状核（RT）这一丘脑皮质活动的关键调节因子对ASD相关行为缺陷的具体贡献。基因敲除小鼠表现出癫痫易感性增加、运动活动增加和重复行为。电生理记录显示RT神经元内丘脑振荡增强和爆发式放电增加，同时T型钙电流升高。体内光纤光度法证实RT群体活动与行为相关的增加。值得注意的是，通过T型钙通道阻滞剂Z944以及通过抑制性DREADD hM4Di的C21激活对RT兴奋性进行药理学和化学遗传学抑制，显著改善了ASD相关行为。这些发现确定RT兴奋性过高是ASD的一个机制驱动因素，并突出了RT作为一个潜在的治疗靶点。
