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Updated: May 22, 2026
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Reversible disruption of pre-pulse inhibition in hypomorphic-inducible and reversible CB1-/- mice
Maria Franca Marongiu1, Daniela Poddie, Susanna Porcu
1Institute of Genetic and Biomedical Research, National Research Council, Monserrato, Italy.
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.
Insights
A new inducible and reversible CB1(-/-) mouse model was developed to study schizophrenia. This model, unlike full knockout mice, shows disrupted pre-pulse inhibition (PPI), a key schizophrenia endophenotype, offering new research avenues.
Area of Science:
- Neuroscience and Psychiatry
- Genetics and Molecular Biology
Background:
- Schizophrenia pathogenesis involves multiple genes, with animal models capturing only specific endophenotypes.
- The cannabinoid receptor 1 (CB1R) is increasingly linked to schizophrenia, necessitating advanced models for study.
- Traditional CB1R knockout ((-/-)) mice have limitations due to compensatory mechanisms.
Purpose of the Study:
- To develop and characterize a novel inducible and reversible, forebrain-specific, hypomorphic CB1R knockout mouse model (IRh-CB1(-/-)).
- To investigate the roles of CB1R in schizophrenia endophenotypes, specifically motor activity and pre-pulse inhibition (PPI) of the startle reflex.
Main Methods:
- Generation of tet-off dependent, tissue-specific CB1R knockout mice (IRh-CB1(-/-)) with hypomorphic re-expression in the forebrain.
- Analysis of motor activity and PPI in wild-type (WT), CB1(-/-), and IRh-CB1(-/-) mice under doxycycline (Dox) and vehicle conditions.
- Assessment of PPI response reversibility upon Dox withdrawal and haloperidol treatment.
Main Results:
- Both CB1(-/-) and IRh-CB1(-/-) mice exhibited increased motor activity compared to WT mice.
- Pre-pulse inhibition (PPI) was significantly disrupted in Dox(+)-induced IRh-CB1(-/-) mice, but not in WT or full CB1(-/-) mice.
- The disrupted PPI in IRh-CB1(-/-) mice was reversible upon Dox withdrawal or haloperidol treatment.
Conclusions:
- The developed IRh-CB1(-/-) mouse is the first inducible and reversible model for studying CB1R's role in schizophrenia endophenotypes.
- This hypomorphic model reveals a specific role for forebrain CB1R in PPI disruption, distinct from full knockout models.
- This novel model offers a valuable tool for in vivo and in vitro research into the endocannabinoid system's function in psychiatric disorders.
