Institute of Neuropathology, Section for Translational Epilepsy Research, Medical Faculty, University of Bonn, Bonn, 53127, Germany
Department of Epileptology, University Hospital Bonn, Bonn, 53127, Germany.
J Neurosci. 2021 Sep 29;41(39):8111-8125. doi: 10.1523/JNEUROSCI.0352-21.2021. Epub 2021 Aug 16.
The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output. The regulatory mechanisms governing the development of dendrites, however, are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. However, its function in neurons is unknown. We show that, during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ third-order dendrites both in male and in female mice. Moreover, we demonstrate that SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown caused a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, whereas excitatory neurotransmission was unaffected. Finally, we show that this mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations revealed significant loss of SLK expression. Overall, the present data identify SLK as a key regulator of both dendritic complexity during development and inhibitory synapse maintenance. We show that dysmorphic neurons of human epileptogenic brain lesions have decreased levels of the Ste20-like kinase (SLK). Decreasing SLK expression in mouse neurons revealed that SLK has essential functions in forming the neuronal dendritic tree and in maintaining inhibitory connections with neighboring neurons.
树突的大小和结构在决定神经元的突触输入如何转化为动作电位输出方面起着重要作用。然而，控制树突发育的调节机制还没有得到充分的理解。进化保守的 Ste20/Hippo 激酶途径被认为在调节树突结构的形成和维持中起着重要作用。该途径的一个关键要素，Ste20 样激酶（SLK），调节非神经元细胞中的细胞骨架动态，在神经元发育过程中强烈表达。然而，它在神经元中的功能是未知的。我们发现，在小鼠皮质神经元的发育过程中，SLK 对于雄性和雌性小鼠中较高阶（≥第三阶）树突的正确发育具有惊人的特异性作用。此外，我们证明 SLK 对于维持兴奋-抑制平衡是必需的。具体而言，SLK 敲低导致抑制性突触的选择性丧失和出生后第 15 天之后的功能抑制，而兴奋性神经传递不受影响。最后，我们表明这种机制可能与人类疾病有关，因为人类皮质畸形中的畸形神经元显示出 SLK 表达的显著丧失。总的来说，本研究数据表明 SLK 是发育过程中树突复杂性和抑制性突触维持的关键调节因子。我们表明，人类癫痫性脑病变中的畸形神经元的 Ste20 样激酶（SLK）水平降低。在小鼠神经元中降低 SLK 表达表明 SLK 在形成神经元树突和维持与邻近神经元的抑制性连接方面具有重要功能。
