title: Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks.
abstract: Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.
authors.affiliation: Cell Adhesion Unit, Division of Neuroscience.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pennucci
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Talpo
authors.affiliation: Cell Adhesion Unit, Division of Neuroscience.
authors.forename: Veronica
authors.initials: V
authors.lastname: Astro
authors.affiliation: Cell Adhesion Unit, Division of Neuroscience.
authors.forename: Valentina
authors.initials: V
authors.lastname: Montinaro
authors.affiliation: Molecular Genetics of Mental Retardation Unit, Division of Neuroscience, IRCSS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Morè
authors.affiliation: Experimental Neurophysiology Unit, INSPE-Institute of Experimental Neurology, Division of Neuroscience, IRCSS San Raffaele Scientific Institute and San Raffaele University, Milano 20132, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cursi
authors.affiliation: Experimental Neurophysiology Unit, INSPE-Institute of Experimental Neurology, Division of Neuroscience, IRCSS San Raffaele Scientific Institute and San Raffaele University, Milano 20132, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Castoldi
authors.affiliation: Cell Adhesion Unit, Division of Neuroscience.
authors.forename: Sara
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Molecular Genetics of Mental Retardation Unit, Division of Neuroscience, IRCSS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Experimental Neurophysiology Unit, INSPE-Institute of Experimental Neurology, Division of Neuroscience, IRCSS San Raffaele Scientific Institute and San Raffaele University, Milano 20132, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marenna
authors.affiliation: Experimental Neurophysiology Unit, INSPE-Institute of Experimental Neurology, Division of Neuroscience, IRCSS San Raffaele Scientific Institute and San Raffaele University, Milano 20132, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cambiaghi
authors.affiliation: Cell Adhesion Unit, Division of Neuroscience.
authors.forename: Diletta
authors.initials: D
authors.lastname: Tonoli
authors.affiliation: Experimental Neurophysiology Unit, INSPE-Institute of Experimental Neurology, Division of Neuroscience, IRCSS San Raffaele Scientific Institute and San Raffaele University, Milano 20132, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Leocani
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Biella
authors.affiliation: Molecular Genetics of Mental Retardation Unit, Division of Neuroscience, IRCSS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: Cell Adhesion Unit, Division of Neuroscience.
authors.forename: Ivan
authors.initials: I
authors.lastname: de Curtis
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D004644:Emotions / Q000502:physiology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D059330:GABAergic Neurons / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000172:deficiency* / Q000235:genetics
chemical_list: D018683:Excitatory Amino Acid Agents; D009419:Nerve Tissue Proteins; D016704:Synapsins; C498771:Rac3 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D005968:Glutamate Decarboxylase
keywords: CB1R; VGAT; hyperactivity; inhibitory synapses; neuronal maturation