1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2].
1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. [3].
Nat Neurosci. 2014 Feb;17(2):240-7. doi: 10.1038/nn.3626. Epub 2014 Jan 19.
The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS-positive neurons and lack of GRIN2B induction in Tbr1(+/-) amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1(+/-) mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition.
神经元特异性转录因子 T 盒脑 1（TBR1）调节大脑发育。在自闭症谱系障碍（ASD）患者中，TBR1 基因的破坏性突变已被反复识别。在这里，我们表明 Tbr1 杂合不足导致杏仁核神经元的轴突投射缺陷，并损害了小鼠的社交互动、超声发声、联想记忆和认知灵活性。Tbr1 基因的一个拷贝缺失改变了 Ntng1、Cntn2 和 Cdh8 的表达，并减少了内外杏仁核之间的连接。这些发育缺陷可能会削弱行为刺激时神经元的激活，这表现在 Tbr1(+/-)杏仁核中 c-FOS 阳性神经元较少且缺乏 GRIN2B 诱导。我们还表明，通过局部输注部分 NMDA 受体激动剂 d-环丝氨酸来上调杏仁核神经元的活性，可以改善 Tbr1(+/-) 小鼠的行为缺陷。我们的研究表明，TBR1 对于调节杏仁核的轴突连接和认知很重要。
