title: Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities.
abstract: Despite evidence for a strong genetic contribution to several major psychiatric disorders, individual candidate genes account for only a small fraction of these disorders, leading to the suggestion that multigenetic pathways may be involved. Several known genetic risk factors for psychiatric disease are related to the regulation of actin polymerization, which plays a key role in synaptic plasticity. To gain insight into and test the possible pathogenetic role of this pathway, we designed a conditional knock-out of the Arp2/3 complex, a conserved final output for actin signaling pathways that orchestrates de novo actin polymerization. Here we report that postnatal loss of the Arp2/3 subunit ArpC3 in forebrain excitatory neurons leads to an asymmetric structural plasticity of dendritic spines, followed by a progressive loss of spine synapses. This progression of synaptic deficits corresponds with an evolution of distinct cognitive, psychomotor, and social disturbances as the mice age. Together, these results point to the dysfunction of actin signaling, specifically that which converges to regulate Arp2/3, as an important cellular pathway that may contribute to the etiology of complex psychiatric disorders.
authors.affiliation: Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical School, Durham, North Carolina, 27710, USA.
authors.forename: Il Hwan
authors.initials: IH
authors.lastname: Kim
authors.forename: Bence
authors.initials: B
authors.lastname: Racz
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Lauren
authors.initials: L
authors.lastname: Burianek
authors.forename: Richard
authors.initials: R
authors.lastname: Weinberg
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yasuda
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Scott H
authors.initials: SH
authors.lastname: Soderling
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000172:deficiency*; D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics; D049229:Dendritic Spines / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D008164:Luminescent Proteins / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D038761:Photobleaching; D015221:Potassium Channels / Q000235:genetics; D000081033:Potassium Channels, Sodium-Activated; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D017470:Receptors, Glutamate / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012919:Social Behavior; D013569:Synapses / Q000235:genetics / Q000473:pathology*; D013997:Time Factors
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; C513333:Arpc3 protein, mouse; D001426:Bacterial Proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C518649:Kcnt2 protein, mouse; D008164:Luminescent Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D011506:Proteins; D022661:RNA, Untranslated; D017470:Receptors, Glutamate; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase
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