Ruiz-Reig Nuria, García-Sánchez Dario, Schakman Olivier, Gailly Philippe, Tissir Fadel
Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Front Mol Neurosci. 2023 Jan 17;15:1110986. doi: 10.3389/fnmol.2022.1110986. eCollection 2022.
Malformation of cortical development (MCD) is a family of neurodevelopmental disorders, which usually manifest with intellectual disability and early-life epileptic seizures. Mutations in genes encoding microtubules (MT) and MT-associated proteins are one of the most frequent causes of MCD in humans. KIF2A is an atypical kinesin that depolymerizes MT in ATP-dependent manner and regulates MT dynamics. In humans, single mutations in KIF2A are associated with MCD with epileptic seizures, posterior pachygyria, microcephaly, and partial agenesis of corpus callosum. In this study, we conditionally ablated KIF2A in forebrain inhibitory neurons and assessed its role in development and function of inhibitory cortical circuits. We report that adult mice with specific deletion of KIF2A in GABAergic interneurons display abnormal behavior and increased susceptibility to epilepsy. KIF2A is essential for tangential migration of cortical interneurons, their positioning in the cerebral cortex, and for formation of inhibitory synapses . Our results shed light on how KIF2A deregulation triggers functional alterations in neuronal circuitries and contributes to epilepsy.
皮质发育畸形（MCD）是一类神经发育障碍疾病，通常表现为智力残疾和早期癫痫发作。编码微管（MT）和MT相关蛋白的基因突变是人类MCD最常见的病因之一。KIF2A是一种非典型驱动蛋白，以ATP依赖的方式使MT解聚并调节MT动力学。在人类中，KIF2A的单基因突变与伴有癫痫发作、后部巨脑回、小头畸形和胼胝体部分发育不全的MCD相关。在本研究中，我们在前脑抑制性神经元中条件性敲除KIF2A，并评估其在抑制性皮质回路发育和功能中的作用。我们报告，在GABA能中间神经元中特异性缺失KIF2A的成年小鼠表现出异常行为，且癫痫易感性增加。KIF2A对于皮质中间神经元的切向迁移、它们在大脑皮质中的定位以及抑制性突触的形成至关重要。我们的结果揭示了KIF2A失调如何触发神经元回路的功能改变并导致癫痫。
