title: Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction.
abstract: Balanced development of excitatory and inhibitory synapses is required for normal brain function, and an imbalance in this development may underlie the pathogenesis of many neuropsychiatric disorders. Compared with the many identified trans-synaptic adhesion complexes that organize excitatory synapses, little is known about the organizers that are specific for inhibitory synapses. We found that Slit and NTRK-like family member 3 (Slitrk3) actS as a postsynaptic adhesion molecule that selectively regulates inhibitory synapse development via trans-interaction with axonal tyrosine phosphatase receptor PTPδ. When expressed in fibroblasts, Slitrk3 triggered only inhibitory presynaptic differentiation in contacting axons of co-cultured rat hippocampal neurons. Recombinant Slitrk3 preferentially localized to inhibitory postsynaptic sites. Slitrk3-deficient mice exhibited decreases in inhibitory, but not excitatory, synapse number and function in hippocampal CA1 neurons and exhibited increased seizure susceptibility and spontaneous epileptiform activity. Slitrk3 required trans-interaction with axonal PTPδ to induce inhibitory presynaptic differentiation. These results identify Slitrk3-PTPδ as an inhibitory-specific trans-synaptic organizing complex that is required for normal functional GABAergic synapse development.
authors.affiliation: Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Hideto
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kei-Ichi
authors.initials: K
authors.lastname: Katayama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sohya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Tuhina
authors.initials: T
authors.lastname: Prasad
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Maya
authors.initials: M
authors.lastname: Ota
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yasuda
authors.forename: Tadaharu
authors.initials: T
authors.lastname: Tsumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Aruga
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Craig
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology*; D017729:Presynaptic Terminals; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C493465:Slc17a7 protein, mouse; C480569:Slitrk protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D005968:Glutamate Decarboxylase