title: Genetic evidence for the adhesion protein IgSF9/Dasm1 to regulate inhibitory synapse development independent of its intracellular domain.
abstract: Normal brain function requires balanced development of excitatory and inhibitory synapses. An imbalance in synaptic transmission underlies many brain disorders such as epilepsy, schizophrenia, and autism. Compared with excitatory synapses, relatively little is known about the molecular control of inhibitory synapse development. We used a genetic approach in mice to identify the Ig superfamily member IgSF9/Dasm1 as a candidate homophilic synaptic adhesion protein that regulates inhibitory synapse development. IgSF9 is expressed in pyramidal cells and subsets of interneurons in the CA1 region of hippocampus. Electrophysiological recordings of acute hippocampal slices revealed that genetic inactivation of the IgSF9 gene resulted in fewer functional inhibitory synapses; however, the strength of the remaining synapses was unaltered. These physiological abnormalities were correlated with decreased expression of inhibitory synapse markers in IgSF9(-/-) mice, providing anatomical evidence for a reduction in inhibitory synapse numbers, whereas excitatory synapse development was normal. Surprisingly, knock-in mice expressing a mutant isoform of IgSF9 lacking the entire cytoplasmic domain (IgSF9(ΔC/ΔC) mice) had no defects in inhibitory synapse development, providing genetic evidence that IgSF9 regulates synapse development via ectodomain interactions rather than acting itself as a signaling receptor. Further, we found that IgSF9 mediated homotypic binding and cell aggregation, but failed to induce synapse formation, suggesting that IgSF9 acts as a cell adhesion molecule (CAM) to maintain synapses. Juvenile IgSF9(-/-) mice exhibited increased seizure susceptibility indicative of an imbalance in synaptic excitation and inhibition. These results provide genetic evidence for a specific role of IgSF9 in inhibitory synapse development/maintenance, presumably by its CAM-like activity.
authors.affiliation: Department of Molecules-Signaling-Development and Synaptic Receptor Trafficking Group, Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany, German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, D-85764 Neuherberg, Germany, Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, D-80336 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany, and Department of Physiology II, University of Bonn, D-53115 Bonn, Germany.
authors.forename: Archana
authors.initials: A
authors.lastname: Mishra
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Traut
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Valentin
authors.initials: V
authors.lastname: Stein
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics*; D007395:Interneurons / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009433:Neural Inhibition / Q000235:genetics*; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism*; D013569:Synapses / Q000235:genetics* / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C486759:Igsf9 protein, mouse; D007136:Immunoglobulins; D009419:Nerve Tissue Proteins