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
Kohtarou Konno
Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Japan
Emily Demchak
Department of Biochemistry and Molecular Biology and Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, United States
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
Takuya Watanabe
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
David G Keener
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
Manabu Abe
Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan
Timmy Le
Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
Kenji Sakimura
Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan
Toshikuni Sasaoka
Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, Niigata, Japan
Takeshi Uemura
Division of Gene Research, Research Center for Supports to Advanced Science, Shinshu University, Nagano, Japan; Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, Japan
Yuka Imamura Kawasawa
Department of Biochemistry and Molecular Biology and Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, United States; Department of Pharmacology Pennsylvania State University College of Medicine, Hershey, United States
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.
