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A new 3-hit mouse model of schizophrenia built on genetic, early and late factors

Abstract : Whether the etiology of schizophrenia remains unknown, its multifactorial aspect is conversely now well admitted. However, most preclinical models of the disease still rely on a mono-factorial construction and do not allow discover unequivocal treatments, particularly for negative and cognitive symptoms. The main interaction factors that have been implicated in schizophrenia are a genetic predisposition and unfavorable environmental factors. Here we propose a new animal model combining a genetic predisposition (1st hit: partial deletion of MAP-6 (Microtubule-associated protein)) with an early postnatal stress (2nd hit: 24h maternal separation at postnatal day 9), and a late cannabinoid exposure during adolescence (3rd hit: tetrahydrocannabinol THC from post-natal day 32 to 52; 8 mg/kg/day). The 2-hit mice displayed spatial memory deficits, decreased cortical thickness and fractional anisotropy of callosal fibers. The 3-hit mice were more severely affected as attested by supplementary deficits such a decrease in spontaneous activity, sociability-related behavior, working memory performances, an increase in anxiety-like behavior, a decrease in hippocampus volume together with impaired integrity of corpus callosum fibers (less axons, less myelin). Taken together, these results show that the new 3-hit model displays several landmarks mimicking negative and cognitive symptoms of schizophrenia, conferring a high relevance for research of new treatments. Moreover, this 3-hit model possesses a strong construct validity, which fits with gene x environment interactions hypothesis of schizophrenia. The 2-hit model, which associates maternal separation with THC exposure in wild-type mice gives a less severe phenotype, and could be useful for research on other forms of psychiatric diseases.
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Contributor : Valentine Bouet <>
Submitted on : Tuesday, December 1, 2020 - 11:38:02 AM
Last modification on : Wednesday, December 2, 2020 - 3:36:53 AM


  • HAL Id : hal-03033208, version 1



Valentine Bouet, Solenn Percelay, Elise Leroux, Boubacar Diarra, Marianne Leger, et al.. A new 3-hit mouse model of schizophrenia built on genetic, early and late factors. Schizophrenia Research, Elsevier, In press. ⟨hal-03033208⟩



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