1] Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA [2] Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa, Iowa City, IA, USA.
Mol Psychiatry. 2013 Oct;18(10):1077-89. doi: 10.1038/mp.2013.71. Epub 2013 May 28.
Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.
自闭症谱系障碍 (ASD) 被认为是由于经典和非经典 Wnt 信号通路的异常而产生的。然而，尚未确定 Wnt 通路基因中的人类变异与 ASD 相关的脑病理学之间存在直接联系。Prickle2 (Pk2) 是一种后突触非经典 Wnt 信号蛋白，已被证明与突触后密度 95 (PSD-95) 相互作用。在这里，我们表明，Prickle2 缺失的小鼠表现出行为异常，包括社交互动改变、学习异常和行为灵活性降低。小鼠海马神经元中 Prickle2 的破坏导致树突分支、突触数量和 PSD 大小减少。与这些发现一致的是，Prickle2 缺失的神经元显示自发性微小突触电流的频率和幅度降低。Prickle2 缺失小鼠的这些行为和生理异常与其他 ASD 小鼠模型中存在的 ASD 样表型一致。在 384 名自闭症患者中，我们鉴定出了两种具有独特的、杂合的、罕见的、非同义 PRICKLE2 变异 (p.E8Q 和 p.V153I) 的个体，这些变异在受影响的兄弟姐妹中共享，并遗传自父亲。与野生型 Prickle2 不同，在 ASD 患者中发现的 Prickle2 变异在形态和电生理测定中表现出缺陷。这些数据表明这些 PRICKLE2 变异导致 Prickle2 功能的严重丧失。这里呈现的数据为 Prickle2 的生物学作用、其行为重要性提供了新的见解，并表明非经典 Wnt 基因（如 PRICKLE2）的破坏可能导致 ASD 下的突触异常。
