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  3. 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

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

  • Neuropharmacology. 2014 Nov;86:133-44. doi: 10.1016/j.neuropharm.2014.07.009.
Rosamaria Orlando 1,  Marina Borro 2,  Marta Motolese 3,  Gemma Molinaro 3,  Sergio Scaccianoce 4,  Alessandra Caruso 4,  Luigi di Nuzzo 4,  Filippo Caraci 5,  Francesco Matrisciano 6,  Anna Pittaluga 7,  Jerome Mairesse 8,  Maurizio Simmaco 2,  Robert Nisticò 4,  James A Monn 9,  Ferdinando Nicoletti 10
Affiliations

Affiliations

  • 1 IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, Italy.
  • 2 NESMOS Department, Advanced Molecular Diagnostic Unit, Sapienza University, Sant'Andrea Hospital, Rome, Italy.
  • 3 IRCCS Neuromed, Pozzilli, Italy.
  • 4 Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
  • 5 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.
  • 6 IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy.
  • 7 Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.
  • 8 Neural Plasticity Team, Université Lille 1, International Associated Laboratory (LIA), France.
  • 9 Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA.
  • 10 IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. Electronic address: ferdinandonicoletti@hotmail.com.
PMID: 25063582 DOI: 10.1016/j.neuropharm.2014.07.009
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.

Keywords

LY354740; LY379268; Prenatal stress; Rab GDI; Schizophrenia.

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