title: mDia and ROCK Mediate Actin-Dependent Presynaptic Remodeling Regulating Synaptic Efficacy and Anxiety.
abstract: Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK), Rho-regulated modulators of actin and myosin, in this process. We find that social isolation induces inactivation of nucleus accumbens (NAc) neurons associated with elevated anxiety-like behavior, and that mDia in NAc neurons is essential in this process. Upon inactivation of cultured neurons, mDia induces circumferential actin filaments around the edge of the synaptic cleft, which contract the presynaptic terminals in a ROCK-dependent manner. Social isolation induces similar mDia-dependent presynaptic contraction at GABAergic synapses from NAc neurons in the ventral tegmental area (VTA) associated with reduced synaptic efficacy. Optogenetic stimulation of NAc neurons rescues the anxiety phenotype, and injection of a specific ROCK inhibitor, Y-27632, into the VTA reverses both presynaptic contraction and the behavioral phenotype. mDia-ROCK signaling thus mediates actin-dependent presynaptic remodeling in inactivated NAc neurons, which underlies synaptic plasticity in emotional behavioral responses.
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. Electronic address: y-deguchi@nagasaki-u.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Deguchi
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Harada
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Shinohara
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Cherasse
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sekiguchi
authors.affiliation: Department of Biological Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Watanabe
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furuyashiki
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. Electronic address: snaru@mfour.med.kyoto-u.ac.jp.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000375:Aging; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D000080865:Formins; D059330:GABAergic Neurons / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000378:metabolism; D062308:Optogenetics; D010641:Phenotype; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012934:Social Isolation; D017557:Ventral Tegmental Area / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D000577:Amides; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; C491463:Diap2 protein, mouse; D000080865:Formins; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases