Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea.
Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Korea.
Cell Rep. 2016 Feb 2;14(4):808-822. doi: 10.1016/j.celrep.2015.12.081. Epub 2016 Jan 14.
The four members of the LRRTM family (LRRTM1-4) are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG) granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.
LRRTM 家族的四个成员（LRRTM1-4）是突触后黏附分子，对于兴奋性突触发育至关重要。它们也与神经精神疾病有关。在这里，我们专注于 LRRTM3，表明两种不同的由选择性剪接产生的 LRRTM3 变体调节 LRRTM3 与 PSD-95 的相互作用，但不影响其促进兴奋性突触的活性。LRRTM3 变体的过表达均增加了齿状回（DG）颗粒神经元中兴奋性突触的密度，而 LRRTM3 的敲低则减少了兴奋性突触的密度。LRRTM3 还以依赖于选择性剪接的方式控制活性调节的 AMPA 受体表面表达。此外，Lrrtm3 敲除小鼠在 DG 颗粒神经元中表现出兴奋性突触密度、兴奋性突触传递和兴奋性的特定改变，但在 CA1 锥体神经元中则没有。最后，LRRTM3 仅需要特定的突触前神经连接蛋白的剪接变体来发挥其促突触形成活性。总的来说，我们的数据强调了 LRRTM 调节中的选择性剪接和差异的突触前配体利用，揭示了兴奋性突触发育的关键调节机制。
