title: An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells.
abstract: Selective synapse development determines how complex neuronal networks in the brain are formed. Complexes of postsynaptic neuroligins and LRRTMs with presynaptic neurexins contribute widely to excitatory synapse development, and mutations in these gene families increase the risk of developing psychiatric disorders. We find that LRRTM4 has distinct presynaptic binding partners, heparan sulfate proteoglycans (HSPGs). HSPGs are required to mediate the synaptogenic activity of LRRTM4. LRRTM4 shows highly selective expression in the brain. Within the hippocampus, we detected LRRTM4 specifically at excitatory postsynaptic sites on dentate gyrus granule cells. LRRTM4(-/-) dentate gyrus granule cells, but not CA1 pyramidal cells, exhibit reductions in excitatory synapse density and function. Furthermore, LRRTM4(-/-) dentate gyrus granule cells show impaired activity-regulated AMPA receptor trafficking. These results identifying cell-type-specific functions and multiple presynaptic binding partners for different LRRTM family members reveal an unexpected complexity in the design and function of synapse-organizing proteins.
authors.affiliation: Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Tabrez J
authors.initials: TJ
authors.lastname: Siddiqui
authors.forename: Parisa Karimi
authors.initials: PK
authors.lastname: Tari
authors.forename: Steven A
authors.initials: SA
authors.lastname: Connor
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dobie
authors.forename: Kevin
authors.initials: K
authors.lastname: She
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabe
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Craig
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018891:Dentate Gyrus / Q000166:cytology*; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051528:Guanylate Kinases; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D016704:Synapsins / Q000378:metabolism
chemical_list: D000596:Amino Acids; C498441:Bsn protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D019812:Heparan Sulfate Proteoglycans; C584075:LRRTM4 protein, mouse; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016704:Synapsins; C098463:dolaisoleucine; D051528:Guanylate Kinases