title: Levels of the Rab GDP dissociation inhibitor (GDI) are altered in the prenatal restrain stress mouse model of schizophrenia and are differentially regulated by the mGlu2/3 receptor agonists, LY379268 and LY354740.
abstract: LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740. Among the few proteins that were differentially influenced by the two drugs, Rab GDP dissociation inhibitor-β (Rab GDIβ) was down-regulated by LY379268 and showed a trend to an up-regulation in response to LY354740. In cultured hippocampal neurons, LY379268 selectively down-regulated the α isoform of Rab GDI. Rab GDI inhibits the activity of the synaptic vesicle-associated protein, Rab3A, and is reduced in the brain of schizophrenic patients. We examined the expression of Rab GDI in mice exposed to prenatal stress ("PRS mice"), which have been described as a putative model of schizophrenia. Rab GDIα protein levels were increased in the hippocampus of PRS mice at postnatal days (PND)1 and 21, but not at PND60. At PND21, PRS mice also showed a reduced depolarization-evoked [(3)H]d-aspartate release in hippocampal synaptosomes. The increase in Rab GDIα levels in the hippocampus of PRS mice was reversed by a 7-days treatment with LY379268 (1 or 10 mg/kg, i.p.), but not by treatment with equal doses of LY354740. These data strengthen the validity of PRS mice as a model of schizophrenia, and show for the first time a pharmacodynamic difference between LY379268 and LY354740 which might be taken into account in an attempt to explain the differential effect of the two drugs across mouse models.
authors: IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, Italy.
authors: Rosamaria
authors: R
authors: Orlando
authors: NESMOS Department, Advanced Molecular Diagnostic Unit, Sapienza University, Sant'Andrea Hospital, Rome, Italy.
authors: Marina
authors: M
authors: Borro
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Marta
authors: M
authors: Motolese
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Gemma
authors: G
authors: Molinaro
authors: Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
authors: Sergio
authors: S
authors: Scaccianoce
authors: Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
authors: Alessandra
authors: A
authors: Caruso
authors: Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
authors: Luigi
authors: L
authors: di Nuzzo
authors: IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, Italy; Department of Educational Sciences, University of Catania, Catania, Italy.
authors: Filippo
authors: F
authors: Caraci
authors: IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy.
authors: Francesco
authors: F
authors: Matrisciano
authors: Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.
authors: Anna
authors: A
authors: Pittaluga
authors: Neural Plasticity Team, Université Lille 1, International Associated Laboratory (LIA), France.
authors: Jerome
authors: J
authors: Mairesse
authors: NESMOS Department, Advanced Molecular Diagnostic Unit, Sapienza University, Sant'Andrea Hospital, Rome, Italy.
authors: Maurizio
authors: M
authors: Simmaco
authors: Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
authors: Robert
authors: R
authors: Nisticò
authors: Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors: James A
authors: JA
authors: Monn
authors: IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. Electronic address: ferdinandonicoletti@hotmail.com.
authors: Ferdinando
authors: F
authors: Nicoletti
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002478:Cells, Cultured; D026603:D-Aspartic Acid / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D040901:Proteomics / Q000379:methods; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D012149:Restraint, Physical; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D026603:D-Aspartic Acid; C104753:eglumetad
keywords: LY354740; LY379268; Prenatal stress; Rab GDI; Schizophrenia