Consequences of postnatal Tshz3 deletion: implications for autism spectrum disorder

We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered cortical expression of genes encoding for synaptic components, electrophysiological and synaptic changes in layer 5 CPNs, impaired corticostriatal glutamate transmission and plasticity, as well as strong ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency. Three independent replicates, each containing cortices from 3-4 mice (P34), were prepared for analysis.我们近期在携带伴自闭症特征综合征的患者中，发现了编码锌指转录因子（Zn-finger transcription factor）的TSHZ3基因存在杂合缺失，并在小鼠模型中证实了Tshz3单倍剂量不足、皮层投射神经元（cortical projection neurons, CPNs）缺陷与自闭症谱系障碍（autism spectrum disorder, ASD）样异常之间的关联。为更深入阐明TSHZ3在大脑正常发育过程中的时空调控需求，我们构建并表征了一种新型小鼠模型：该模型可从出生后第2-3天起，在投射神经元中实现条件性Tshz3基因敲除。该模型小鼠表现出突触相关组分编码基因的皮层表达异常、第五层皮层投射神经元的电生理与突触改变、受损的皮层纹状体谷氨酸能传递及突触可塑性，以及显著的ASD相关行为缺陷。本研究通过揭示TSHZ3在皮层纹状体环路发育与功能中的关键产后作用——该环路或为ASD发病机制的决定性因素之一——不仅提供了一种新型ASD模型，还为TSHZ3单倍剂量不足相关综合征开辟了产后早期治疗窗口的可能性。本次分析共设置3次独立重复实验，每次实验均取材自3-4只出生后第34天（P34）小鼠的皮层组织。