title: Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2.
abstract: BACKGROUND
  The majority of neurons within the central nervous system receive their excitatory inputs via small, actin-rich protrusions called dendritic spines. Spines can undergo rapid morphological alterations according to synaptic activity. This mechanism is implicated in learning and memory formation as it is ultimately altering the number and distribution of receptors and proteins at the post-synaptic membrane, thereby regulating synaptic input. The Rho-family GTPases play an important role in regulating this spine plasticity by the interaction with cytoskeletal components and several signaling pathways within the spine compartment. Rho-GAP interacting CIP4 homologue2/RICH2 is a Rho-GAP protein regulating small GTPases and was identified as an interaction partner of the scaffolding protein SHANK3 at post-synaptic densities.
  
  
  RESULTS
  Here, we characterize the loss of RICH2 in a novel mouse model. Our results show that RICH2 KO animals display a selective and highly significant fear of novel objects and increased stereotypic behavior as well as impairment of motor learning. We found an increase in multiple spine synapses in the hippocampus and cerebellum along with alterations in receptor composition and actin polymerization. Furthermore, we observed that the loss of RICH2 leads to a disinhibition of synaptic RAC1 in vivo.
  
  
  CONCLUSIONS
  The results are in line with the reported role of RAC1 activity being essential for activity-dependent spine enlargement. Since SHANK3 mutations are known to be causative for neuropsychiatric diseases of the Autism Spectrum (ASD), a disintegrated SHANK3/RICH2 complex at synaptic sites might at least in part be responsible for abnormal spine formation and plasticity in ASDs.
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Department, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany.
authors.forename: Tasnuva
authors.initials: T
authors.lastname: Sarowar
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Grabrucker
authors.affiliation: Department of Anesthesiology, University of Ulm, 89081, Ulm, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Föhr
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Department, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mangus
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Department, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany.
authors.forename: Matti
authors.initials: M
authors.lastname: Eckert
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Bockmann
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany. tobias.boeckers@uni-ulm.de.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Department, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany. andreas.grabrucker@uni-ulm.de.|Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, D-89081, Ulm, Germany. andreas.grabrucker@uni-ulm.de.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology*; D020690:GTPase-Activating Proteins / Q000172:deficiency*; D005971:Glutamates / Q000378:metabolism; D008817:Mice, Mutant Strains; D009043:Motor Activity; D010698:Phobic Disorders / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D005971:Glutamates; C000611528:RICH2 protein, mouse
keywords: Autism; Dendritic spine; Neophobia; Rac1; Shank3; Small GTPase; Spine morphogenesis, Phobia