title: Netrin-G/NGL complexes encode functional synaptic diversification.
abstract: Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity.
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsukawa
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akiyoshi-Nishimura
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: IDINE, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, 13071 Albacete, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Yaguchi
authors.affiliation: Research Resource Center, RIKEN BSI, Wako, Saitama, 351-0198, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Sano
authors.affiliation: Division of Cerebral Structure, National Institute for Physiological Science, Okazaki 444-8787, Japan, and IST Austria, 3400 Klosterneuburg, Austria.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shigemoto
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakashiba
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan, sitohara@brain.riken.jp.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
mesh_terms: D000818:Animals; D003712:Dendrites / Q000648:ultrastructure; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D000075385:Netrins; D018408:Patch-Clamp Techniques; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure
chemical_list: C503332:LRRC4 protein, mouse; C000594607:NGL1 protein, mouse; D009419:Nerve Tissue Proteins; D000075385:Netrins; C456263:Ntng2 protein, mouse; D011956:Receptors, Cell Surface; C413653:netrin-G1
keywords: excitatory synapse; mice; netrin-G1; netrin-G2; pathway specificity; trans-synaptic adhesion molecule