title: Reversible disruption of pre-pulse inhibition in hypomorphic-inducible and reversible CB1-/- mice.
abstract: Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout ((-/-)) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1(-/-) mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1(-/-)) only in absence of doxycycline (Dox). In such mice, under Dox(+) or vehicle, as well as in wild-type (WT) and CB1(-/-), two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1(-/-) and IRh-CB1(-/-) showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1(-/-) animals, was on the contrary highly and significantly disrupted only in Dox(+) IRh-CB1(-/-) mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1(-/-) mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1(-/-) mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders.
authors.affiliation: Institute of Genetic and Biomedical Research, National Research Council, Monserrato, Italy.
authors.forename: Maria Franca
authors.initials: MF
authors.lastname: Marongiu
authors.forename: Daniela
authors.initials: D
authors.lastname: Poddie
authors.forename: Susanna
authors.initials: S
authors.lastname: Porcu
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Manchinu
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Castelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Sogos
authors.forename: Valentina
authors.initials: V
authors.lastname: Bini
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Caredda
authors.forename: Maria
authors.initials: M
authors.lastname: Collu
authors.forename: Maria Serafina
authors.initials: MS
authors.lastname: Ristaldi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology*; D058068:Endophenotypes; D005786:Gene Expression Regulation / Q000187:drug effects*; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009841:Oligonucleotides / Q000235:genetics; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D009841:Oligonucleotides; D043884:Receptor, Cannabinoid, CB1; D004318:Doxycycline