Neural Control of Movement Lab, HEST, ETH Zürich, Winterthurerstrasse 190, Zurich, Switzerland.
Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Str. 27, Zurich, Switzerland.
Cereb Cortex. 2018 Jul 1;28(7):2495-2506. doi: 10.1093/cercor/bhy046.
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.
自闭症谱系障碍 (ASD) 是一组复杂的神经发育障碍，目前尚无针对性的治疗方法。据认为，发育过程中调节迁移和突触形成的基因改变会影响神经回路的形成，并导致特定回路中异常的连接，从而导致异常行为。然而，尚不清楚异常发育轨迹是否针对特定的自闭症风险基因。我们使用 MRI 来探测脆性 X (Fmr1-/y) 和接触蛋白相关 (CNTNAP2-/-) 基因敲除小鼠从儿童期到成年期的功能和结构连接变化。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中表现出皮质皮质和皮质纹状体回路的强烈连接不足表型，这种表型一直持续到成年期。相反，CNTNAP2-/- 小鼠在出生后的早期发育过程中，海马体和纹状体区域只有微小的差异，而在青春期到成年期之间，前额叶和边缘通路则出现了严重的连接缺陷。这些发现得到了病毒追踪和电子显微镜方法的支持，并定义了自闭症谱系中 2 种明显不同的连接表型。我们得出结论，ASD 的遗传背景强烈影响受影响的回路、表型的性质以及相关变化的发育时间进程。
