title: The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.
abstract: Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: E Anne
authors.initials: EA
authors.lastname: Martin
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Muralidhar
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Diégo Cordero
authors.initials: DC
authors.lastname: Cervantes
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Raunak
authors.initials: R
authors.lastname: Basu
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Taylor
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hunter
authors.affiliation: Department of Neurology, Columbia University, New York City, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Cutforth
authors.affiliation: Neurobiology Section, Division of Biological Sciences, University of California, San Diego, San Diego, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wilke
authors.affiliation: Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Anirvan
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Williams
mesh_terms: D000818:Animals; D002460:Cell Line; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000196:embryology / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D013569:Synapses / Q000378:metabolism*
chemical_list: C474214:Kirrel3 protein, mouse; D008565:Membrane Proteins
keywords: Kirrel3; cell adhesion; hippocampus; mouse; neuroscience; synaptic specificity