title: nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology.
abstract: Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spine-synapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott-Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder.
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 01030, South Korea;
authors.forename: Sang-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 01030, South Korea; KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, South Korea;
authors.forename: Yoonju
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Interdisciplinary Program in Neuroscience, Seoul National University College of Medicine, Seoul 01030, South Korea;
authors.forename: Jeong-Kyu
authors.initials: JK
authors.lastname: Han
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, South Korea;
authors.forename: Hoyong
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 01030, South Korea;
authors.forename: Unghwi
authors.initials: U
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 01030, South Korea;
authors.forename: Myeongsu
authors.initials: M
authors.lastname: Na
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 01030, South Korea;
authors.forename: Soomin
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, South Korea;
authors.forename: ChiHye
authors.identifier: 0000-0002-3104-2399
authors.initials: C
authors.lastname: Chung
authors.affiliation: Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, 00185 Rome, Italy; Department of Biology and Biotechnology, University of Rome "Sapienza", 00185 Rome, Italy sunghoe@snu.ac.kr gianluca.cestra@uniroma1.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Cestra
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea; Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 01030, South Korea; Interdisciplinary Program in Neuroscience, Seoul National University College of Medicine, Seoul 01030, South Korea; sunghoe@snu.ac.kr gianluca.cestra@uniroma1.it.
authors.forename: Sunghoe
authors.initials: S
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020033:Protein Isoforms; C490754:Sorbs2 protein, rat
keywords: actin; bipolar disorder; dendritic spines; excitatory synapse; nArgBP2