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Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex

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Abstract

Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.

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Acknowledgements

We thank Flávia Salata (USP), Sulo Kolehmainen (UH), and Outi Nikkila (UH) for their technical support and Prof. Eduardo Brandt de Oliveira (Department of Biochemistry, Ribeirão Preto Medical School, USP) for his insightful comments.

Funding

This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo—Fapesp (no. 2012/17626-2), Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (no. 471382/2011-6), and European Research Council (iPlasticity, no. 322742); none of the mentioned agencies had any role on experimental design, data analysis, or the preparation and submission of the present manuscript.

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  1. C. R. A. F. Diniz and P. C. Casarotto contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil

    C. R. A. F. Diniz, C. Becari, M. C. O. Salgado, L. B. M. Resstel, F. S. Guimarães & P. C. Casarotto

  2. Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil

    C. Becari & H. C. Salgado

  3. Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    C. Biojone & S. R. L. Joca

  4. Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

    C. Becari

  5. Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Viikinkaari 4, Helsinki, Finland

    A. Lesnikova, C. Biojone, E. Castrén & P. C. Casarotto

  6. Translational Neuropsychiatric Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    S. R. L. Joca

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  1. C. R. A. F. Diniz
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Correspondence to P. C. Casarotto.

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Diniz, C.R.A.F., Becari, C., Lesnikova, A. et al. Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex. Mol Neurobiol 55, 7062–7071 (2018). https://doi.org/10.1007/s12035-018-0902-6

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