Ehrmann Ingrid, Gazzara Matthew R, Pagliarini Vittoria, Dalgliesh Caroline, Kheirollahi-Chadegani Mahsa, Xu Yaobo, Cesari Eleonora, Danilenko Marina, Maclennan Marie, Lowdon Kate, Vogel Tanja, Keskivali-Bond Piia, Wells Sara, Cater Heather, Fort Philippe, Santibanez-Koref Mauro, Middei Silvia, Sette Claudio, Clowry Gavin J, Barash Yoseph, Cunningham Mark O, Elliott David J
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep. 2016 Dec 20;17(12):3269-3280. doi: 10.1016/j.celrep.2016.12.002.
The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.
大脑由数万亿个突触连接组成，这些连接共同形成正常脑功能和行为所需的神经网络。SLM2是一个保守的RNA结合蛋白家族的成员，该家族包括Sam68和SLM1，它们控制Neurexin1 - 3前体mRNA的剪接。SLM2是否影响神经网络活动尚不清楚。在这里，我们发现SLM2的水平由一个稳态反馈控制途径维持，该途径早于SLM2和Sam68的分化。SLM2还控制Tomosyn2、LysoPLD/ATX、Dgkb、Kif21a和Cask的剪接，它们各自对突触功能都很重要。在Slm2基因敲除小鼠中，依赖于表达SLM2的锥体神经元和中间神经元之间突触连接的皮质神经网络活动减少。此外，这些小鼠表现出焦虑，识别新物体的能力下降。我们的数据揭示了一条SLM2稳态自我调节途径，该途径控制脑网络活动和行为。
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