title: Disruption of ArhGAP15 results in hyperactive Rac1, affects the architecture and function of hippocampal inhibitory neurons and causes cognitive deficits.
abstract: During brain development, the small GTPases Rac1/Rac3 play key roles in neuronal migration, neuritogenesis, synaptic formation and plasticity, via control of actin cytoskeleton dynamic. Their activity is positively and negatively regulated by GEFs and GAPs molecules, respectively. However their in vivo roles are poorly known. The ArhGAP15 gene, coding for a Rac-specific GAP protein, is expressed in both excitatory and inhibitory neurons of the adult hippocampus, and its loss results in the hyperactivation of Rac1/Rac3. In the CA3 and dentate gyrus (DG) regions of the ArhGAP15 mutant hippocampus the CR+, PV+ and SST+ inhibitory neurons are reduced in number, due to reduced efficiency and directionality of their migration, while pyramidal neurons are unaffected. Loss of ArhGAP15 alters neuritogenesis and the balance between excitatory and inhibitory synapses, with a net functional result consisting in increased spike frequency and bursts, accompanied by poor synchronization. Thus, the loss of ArhGAP15 mainly impacts on interneuron-dependent inhibition. Adult ArhGAP15-/-mice showed defective hippocampus-dependent functions such as working and associative memories. These findings indicate that a normal architecture and function of hippocampal inhibitory neurons is essential for higher hippocampal functions, and is exquisitely sensitive to ArhGAP15-dependent modulation of Rac1/Rac3.
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zamboni
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Armentano
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sarò
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ciraolo
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Germena
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Umbach
authors.affiliation: Institute for Neuroscience, CNR Milano, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.affiliation: Institute for Neuroscience, CNR Milano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: Department of Drug Science, University of Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Carabelli
authors.affiliation: Department of Drug Science, University of Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gavello
authors.affiliation: IRCSS San Raffaele Scientific Institute and San Raffaele University, Division of Neuroscience, Milano, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: IRCSS San Raffaele Scientific Institute and San Raffaele University, Division of Neuroscience, Milano, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: IRCSS San Raffaele Scientific Institute and San Raffaele University, Division of Neuroscience, Milano, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: de Curtis
authors.affiliation: Department of Neurosciences, University of Turin &Div. of Neurology and Neurorehabilitation, S.Giuseppe Hospital, Istituto Auxologico Italiano IRCCS, Piancavallo (VB), Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: El-Assawi
authors.affiliation: Department of Neurosciences, University of Turin &Div. of Neurology and Neurorehabilitation, S.Giuseppe Hospital, Istituto Auxologico Italiano IRCCS, Piancavallo (VB), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.affiliation: Department of Neurosciences, University of Turin &Div. of Neurology and Neurorehabilitation, S.Giuseppe Hospital, Istituto Auxologico Italiano IRCCS, Piancavallo (VB), Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Priano
authors.affiliation: Department of Pharmaceutical and Pharmacological Science, University of Padova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy.
authors.forename: Giorgio R
authors.initials: GR
authors.lastname: Merlo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D007395:Interneurons / Q000473:pathology; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008817:Mice, Mutant Strains; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C000628040:Arhgap15 protein, mouse; D020690:GTPase-Activating Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C498771:Rac3 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein