Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
J Neurosci. 2013 Feb 27;33(9):4055-65. doi: 10.1523/JNEUROSCI.4428-12.2013.
Invertebrate studies have highlighted a role for EH and SH3 domain Intersectin (Itsn) proteins in synaptic vesicle recycling and morphology. Mammals have two Itsn genes (Itsn1 and Itsn2), both of which can undergo alternative splicing to include DBL/PH and C2 domains not present in invertebrate Itsn proteins. To probe for specific and redundant functions of vertebrate Itsn genes, we generated Itsn1, Itsn2, and double mutant mice. While invertebrate mutants showed severe synaptic abnormalities, basal synaptic transmission and plasticity were unaffected at Schaffer CA1 synapses in mutant mice. Surprisingly, intercortical tracts-corpus callosum, ventral hippocampal, and anterior commissures-failed to cross the midline in mice lacking Itsn1, but not Itsn2. In contrast, tracts extending within hemispheres and those that decussate to more caudal brain segments appeared normal. Itsn1 mutant mice showed severe deficits in Morris water maze and contextual fear memory tasks, whereas mice lacking Itsn2 showed normal learning and memory. Thus, coincident with the acquisition of additional signaling domains, vertebrate Itsn1 has been functionally repurposed to also facilitate interhemispheric connectivity essential for high order cognitive functions.
无脊椎动物研究强调了 EH 和 SH3 结构域相互作用蛋白（Itsn）在突触囊泡再循环和形态中的作用。哺乳动物有两个 Itsn 基因（Itsn1 和 Itsn2），它们都可以通过选择性剪接包括 DBL/PH 和 C2 结构域，这些结构域不存在于无脊椎动物 Itsn 蛋白中。为了探究脊椎动物 Itsn 基因的特定和冗余功能，我们生成了 Itsn1、Itsn2 和双突变小鼠。虽然无脊椎动物突变体显示出严重的突触异常，但在突变小鼠的 Schaffer CA1 突触中，基础突触传递和可塑性没有受到影响。令人惊讶的是，缺乏 Itsn1 的小鼠中，皮质间束-胼胝体、腹侧海马和前连合未能穿过中线，但缺乏 Itsn2 的小鼠则没有。相比之下，在半球内延伸的束以及向更尾侧脑段交叉的束似乎正常。Itsn1 突变小鼠在 Morris 水迷宫和情境恐惧记忆任务中表现出严重的缺陷，而缺乏 Itsn2 的小鼠则表现出正常的学习和记忆。因此，随着额外信号转导结构域的获得，脊椎动物 Itsn1 的功能已经被重新利用，以促进对高级认知功能至关重要的半球间连接。
