Uchigashima Motokazu, Konno Kohtarou, Demchak Emily, Cheung Amy, Watanabe Takuya, Keener David G, Abe Manabu, Le Timmy, Sakimura Kenji, Sasaoka Toshikuni, Uemura Takeshi, Imamura Kawasawa Yuka, Watanabe Masahiko, Futai Kensuke
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
Department of Cellular Neuropathology, Brain Research Institute, Niigata University, Niigata, Japan.
Elife. 2020 Dec 23;9:e59545. doi: 10.7554/eLife.59545.
Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn signaling generates distinct functional properties at synapses.
突触的形成和调节需要突触前和突触后蛋白之间的信号相互作用，尤其是细胞粘附分子（CAMs）。有人提出，作为突触后CAMs的神经连接蛋白（Nlgns）的功能依赖于与作为突触前CAMs的神经配素（Nrxns）形成反式突触复合物。Nlgn3是一种独特的Nlgn异构体，定位于兴奋性和抑制性突触。然而，通过Nrxn相互作用介导的Nlgn3功能尚不清楚。在这里，我们证明Nlgn3定位于与表达囊泡谷氨酸转运体3（VGT3+）的抑制性终末相对的突触后位点，并在小鼠器官型脑片培养物中调节VGT3+抑制性中间神经元介导的突触传递。对中间神经元的基因表达分析表明，与其他中间神经元相比，αNrxn1+AS4剪接异构体在VGT3+中间神经元中高表达。最重要的是，突触后Nlgn3需要VGT3+中间神经元中表达的突触前αNrxn1+AS4来调节抑制性突触传递。我们的结果表明，特定的Nlgn-Nrxn信号在突触处产生不同的功能特性。
