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Neonatal Rotenone Administration Induces Psychiatric Disorder-Like Behavior and Changes in Mitochondrial Biogenesis and Synaptic Proteins in Adulthood

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Abstract

Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism, we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5–P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adulthood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behavioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.

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Acknowledgments

We thank Prof. Dr. Fabio Cardoso Cruz from the Pharmacology Department at Federal University of São Paulo (UNIFESP), for letting us use passive avoidance apparatus. We also thank the staff of the animal facilities for excellent animal care and the technicians for the support.

The Integrity of Research and Reporting

All experimental procedures, as mentioned previously, were done in accordance with the ethical principles for the use of laboratory animals.

Funding

This work was supported by São Paulo Research Foundation (FAPESP) (ref. 2015/02041-1) and Fundação de Amparo à Pesquisa of Santa Casa de São Paulo School of Medical Science (FCMSCSP) (2015–2016). AS was supported by PROSUC/CAPES, JMCY was an undergraduate student, ACR is under PhD FAPESP fellowship (2015/268200), MDB was supported by CAPES and FAPESP/Master (2016/12039-7), and EH is supported by Master CAPES fellowship.

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Authors and Affiliations

  1. Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil

    Amanda Siena, Jéssica Mayumi Camargo Yuzawa, Elisandra Henrique & Mariana Dutra Brito

  2. Department of Pharmacology, University of Sao Paulo, Sao Paulo, Brazil

    Amanda Siena & Tatiana Rosado Rosenstock

  3. Federal University of São Paulo, São Paulo, Brazil

    Aline Camargo Ramos

  4. Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, Brazil

    Mariana Bendlin Calvazara

  5. Institute of Cancer and Genomic Science/College of Medical and Dental Science, University of Birmingham, Birmingham, B15 2TT, UK

    Tatiana Rosado Rosenstock

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  1. Amanda Siena
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  4. Elisandra Henrique
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Contributions

AS performed all experiments regarding mitochondrial function (functional experiments, western blot and qPCR) and behavioral tests, in addition to the analysis and the statistics. AS also wrote this manuscript. JMCY contributed to oxygen consumption experiments. JMCY, EH, and ACR performed behavioral tests. MDB contributed with qPCR experiments. MBC assisted in the discussion and statistics. TRR designed the study, wrote the protocols, revised the manuscript, and wrote the final version of it.

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Correspondence to Tatiana Rosado Rosenstock.

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Highlights

• Neonatal rotenone exposure induces psychiatric-like phenotype in adulthood

• Neonatal rotenone decreases mitochondrial biogenesis in adult animals

• Rotenone in neonates diminishes Nrf1 expression in P60 and P120 rats

• Neonatal rotenone prompts acute NFE2L2 activation in cortex

• Rotenone in neonates changes synaptic proteins in adulthood

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Siena, A., Yuzawa, J.M.C., Ramos, A.C. et al. Neonatal Rotenone Administration Induces Psychiatric Disorder-Like Behavior and Changes in Mitochondrial Biogenesis and Synaptic Proteins in Adulthood. Mol Neurobiol 58, 3015–3030 (2021). https://doi.org/10.1007/s12035-021-02317-w

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