Center for Neuroscience Research, Children's Research Institute, Children's National Health System, Washington, DC.
Children's Center for Autism Spectrum Disorders, Children's National Health System, Rockville, Maryland.
Autism Res. 2019 Feb;12(2):200-211. doi: 10.1002/aur.2051. Epub 2018 Dec 17.
Amygdala dysfunction has been implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Previous studies in mice and humans, respectively, have linked Pac1r/PAC1R function to social behavior and PTSD-susceptibility. Based on this connection to social and emotional processing and the central role played by the amygdala in ASD, we examined a putative role for PAC1R in social deficits in ASD and determined the pattern of gene expression in the developing mouse and human amygdala. We reveal that Pac1r/PAC1R is expressed in both mouse and human amygdala from mid-neurogenesis through early postnatal stages, critical time points when altered brain trajectories are hypothesized to unfold in ASD. We further find that parents of autistic children carrying a previously identified PTSD-risk genotype (CC) report greater reciprocal social deficits compared to those carrying the non-risk GC genotype. Additionally, by exploring resting-state functional connectivity differences in a subsample of the larger behavioral sample, we find higher functional connectivity between the amygdala and right middle temporal gyrus in individuals with the CC risk genotype. Thus, using multimodal approaches, our data reveal that the amygdala-expressed PAC1R gene may be linked to severity of ASD social phenotype and possible alterations in brain connectivity, therefore potentially acting as a modifier of amygdala-related phenotypes. Autism Res 2019, 12: 200-211 © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this multimodal study across mouse and human, we examined expression patterns of Pac1r/PAC1R, a gene implicated in social behavior, and further explored whether a previously identified human PTSD-linked mutation in PAC1R can predict brain connectivity and social deficits in ASD. We find that PAC1R is highly expressed in the both the mouse and human amygdala. Furthermore, our human data suggest that PAC1R genotype is linked to severity of social deficits and functional amygdala connectivity in ASD.
杏仁核功能障碍与许多神经发育障碍有关，包括自闭症谱系障碍 (ASD)。分别在小鼠和人类中的先前研究将 Pac1r/PAC1R 功能与社交行为和 PTSD 易感性联系起来。基于这种与社交和情绪处理的联系以及杏仁核在 ASD 中的核心作用，我们研究了 PAC1R 在 ASD 社交缺陷中的潜在作用，并确定了发育中小鼠和人类杏仁核中的基因表达模式。我们揭示了 Pac1r/PAC1R 在从中神经发生到早期产后阶段的小鼠和人类杏仁核中都有表达，这是假设在 ASD 中改变的大脑轨迹展开的关键时间点。我们进一步发现，携带先前确定的 PTSD 风险基因型 (CC) 的自闭症儿童的父母报告了更大的互惠社交缺陷，而携带非风险 GC 基因型的父母则没有。此外，通过探索更大行为样本中亚样本的静息状态功能连接差异，我们发现 CC 风险基因型个体的杏仁核与右侧颞中回之间的功能连接更高。因此，通过使用多模态方法，我们的数据表明，表达于杏仁核的 PAC1R 基因可能与 ASD 社会表型的严重程度以及大脑连接的可能改变有关，因此可能作为与杏仁核相关表型的修饰基因。自闭症研究 2019, 12: 200-211 © 2018 自闭症国际研究协会，威利期刊，公司。
