Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, United States of America.
PLoS One. 2018 Jun 19;13(6):e0199399. doi: 10.1371/journal.pone.0199399. eCollection 2018.
The FoxP2 transcription factor and its target genes have been implicated in developmental brain diseases with a prominent language component, such as developmental verbal dyspraxia and specific language impairment. How FoxP2 affects neural circuitry development remains poorly understood. The sushi domain protein SRPX2 is a target of FoxP2, and mutations in SRPX2 are associated with language defects in humans. We have previously shown that SRPX2 is a synaptogenic protein that increases excitatory synapse density. Here we provide the first characterization of mice lacking the SRPX2 gene, and show that these mice exhibit defects in both neural circuitry and communication and social behaviors. Specifically, we show that mice lacking SRPX2 show a specific reduction in excitatory VGlut2 synapses in the cerebral cortex, while VGlut1 and inhibitory synapses were largely unaffected. SRPX2 KO mice also exhibit an abnormal ultrasonic vocalization ontogenetic profile in neonatal pups, and reduced preference for social novelty. These data demonstrate a functional role for SRPX2 during brain development, and further implicate FoxP2 and its targets in regulating the development of vocalization and social circuits.
FoxP2 转录因子及其靶基因与具有明显语言成分的发育性脑疾病有关，例如发育性言语运动障碍和特定语言损伤。FoxP2 如何影响神经回路发育仍知之甚少。 sushi 结构域蛋白 SRPX2 是 FoxP2 的靶标，SRPX2 突变与人类的语言缺陷有关。我们之前曾表明，SRPX2 是一种促进突触形成的蛋白质，可增加兴奋性突触密度。在这里，我们首次对缺乏 SRPX2 基因的小鼠进行了特征描述，并表明这些小鼠在神经回路以及交流和社交行为方面均存在缺陷。具体来说，我们发现缺乏 SRPX2 的小鼠在大脑皮层中表现出兴奋性 VGlut2 突触的特异性减少，而 VGlut1 和抑制性突触基本不受影响。SRPX2 KO 小鼠在新生幼鼠中也表现出异常的超声发声个体发生模式，并降低了对社交新颖性的偏好。这些数据表明 SRPX2 在大脑发育过程中具有功能作用，并进一步表明 FoxP2 及其靶标在调节发声和社交回路的发育中具有重要作用。
