Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.
Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.
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DOI：
10.1093/cercor/bhy046
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发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Wenderoth N
中科院分区：
文献类型：
--
作者：
Zerbi V;Ielacqua GD;Markicevic M;Haberl MG;Ellisman MH;A-Bhaskaran A;Frick A;Rudin M;Wenderoth N
自闭症谱系障碍(ASD)是一组复杂的神经发育障碍，目前还没有针对性的治疗方法。人们认为，在发育过程中，调节迁移和突触形成的基因的变化会影响神经回路的形成，并导致不同回路之间的异常连接，这是异常行为的基础。然而，对于给定的自闭症风险基因，不同的发展轨迹是否具有特定的电路特性尚不清楚。我们使用磁共振成像来探测脆性X基因(Fmr1−/y)和连接蛋白相关基因(CNTNAP2−/−)基因敲除小鼠从童年到成年的功能和结构连接性的变化。年轻的Fmr1−/y小鼠(出生后30天)在与感觉信息处理相关的区域的皮质和皮质纹状体回路中表现出强大的低连接性表型，并一直保持到成年。相反，在CNTNAP2−/−小鼠出生后的早期发育过程中，只有海马区和纹状体区域存在微小的差异，而前额叶和边缘通路的主要连接缺陷在青春期和成年期之间发展起来。这些发现得到了病毒追踪和电子显微镜方法的支持，并在自闭症谱系中定义了两个明显不同的连接内表型。我们得出结论，ASD的遗传背景强烈影响着哪些回路受到最大影响，表型的性质，以及相关变化的发育时间进程。
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1−/y) and contactin-associated (CNTNAP2−/−) knockout mice. Young Fmr1−/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2−/− mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.
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聚类自闭症：在26个小鼠模型中使用神经解剖学差异来深入了解异质性。
影响因子：
11
作者：
Ellegood, J.;Anagnostou, E.;Babineau, B. A.;Crawley, J. N.;Lin, L.;Genestine, M.;DiCicco-Bloom, E.;Lai, J. K. Y.;Foster, J. A.;Penagarikano, O.;Geschwind, D. H.;Pacey, L. K.;Hampson, D. R.;Laliberte, C. L.;Mills, A. A.;Tam, E.;Osborne, L. R.;Kouser, M.;Espinosa-Becerra, F.;Xuan, Z.;Powell, C. M.;Raznahan, A.;Robins, D. M.;Nakai, N.;Nakatani, J.;Takumi, T.;van Eede, M. C.;Kerr, T. M.;Muller, C.;Blakely, R. D.;Veenstra-VanderWeele, J.;Henkelman, R. M.;Lerch, J. P.
通讯作者：
Lerch, J. P.
影响因子：
4.2
作者：
Alaerts, Kaat;Woolley, Daniel G.;Wenderoth, Nicole
通讯作者：
Wenderoth, Nicole
影响因子：
25
作者：
Goncalves, J. Tiago;Anstey, James E.;Golshani, Peyman;Portera-Cailliau, Carlos
通讯作者：
Portera-Cailliau, Carlos
DOI：
10.1126/science.aac9698
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ferenczi EA;Zalocusky KA;Liston C;Grosenick L;Warden MR;Amatya D;Katovich K;Mehta H;Patenaude B;Ramakrishnan C;Kalanithi P;Etkin A;Knutson B;Glover GH;Deisseroth K
通讯作者：
Deisseroth K
影响因子：
5.3
作者：
Belmonte, MK;Allen, G;Webb, SJ
通讯作者：
Webb, SJ