Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice. We used Tbr1+/− mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1+/− mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Tbr1+/− mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1+/− olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1+/− mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1+/− mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency. Tbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1+/− mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.

中文翻译：

---

自闭症致病基因Tbr1的单倍剂量不足削弱小鼠嗅觉歧视和嗅觉系统的神经元激活

自闭症谱系障碍（ASD）表现出两类核心症状，即社交和沟通障碍以及重复行为和感觉异常。我们之前的研究表明，TBR1是ASD的致病基因，可控制轴突投射和杏仁核的神经元激活，并调节小鼠模型中的社交互动和人声交流。通过D-环丝氨酸治疗（一种N-甲基-D-天冬氨酸受体（NMDAR）激动剂）增加神经活动，可以缓解Tbr1单倍体功能不全引起的行为缺陷。在此报告中，我们调查了TBR1在调节嗅觉中的作用，并测试了D-环丝氨酸是否还能改善Tbr1突变小鼠的嗅觉缺陷。我们使用Tbr1 +/-小鼠作为模型来研究TBR1在嗅觉感觉和非社会气味识别中的功能。我们采用行为分析来表征Tbr1 +/-小鼠的嗅觉缺陷。磁共振成像（MRI）和组织学分析用于表征解剖特征。进行免疫染色以进一步分析嗅球中TBR1亚家族成员（即TBR1，TBR2和TBX21），中间神经元种群和树突异常表达的差异。最后，C-FOS染色用于监测气味刺激后嗅觉系统的神经元激活。Tbr1 +/-小鼠表现出较小的嗅球和前连合，减少了中神经元数量，并且嗅球中的二尖瓣细胞的树突形态异常。Tbr1单倍体不足会特别影响嗅觉辨别力，但不会损害嗅觉。Tbr1 +/-嗅球的肾小球层中，气味刺激后神经元的激活减少。此外，尽管梨形和周围神经皮层的大小不受Tbr1缺乏的影响，但响应于气味刺激，在这两个皮质区域神经元的激活减少了。这些结果表明，Tbr1 +/-小鼠的嗅球神经元激活受到损害，嗅球与上层嗅觉系统之间的连通性不良。NMDAR激动剂D-环丝氨酸的全身给药改善了Tbr1 +/-小鼠的嗅觉辨别，提示增加的神经元活性对Tbr1缺乏症具有有益的作用。Tbr1调节嗅觉系统中的神经回路和活动，以控制嗅觉。