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

Author(s)

Siena, Amanda ^{[1, 2]} ; Yuzawa, Jessica Mayumi Camargo ^[2] ; Ramos, Aline Camargo ^[3] ; Henrique, Elisandra ^[2] ; Brito, Mariana Dutra ^[2] ; Calvazara, Mariana Bendlin ^[4] ; Rosenstock, Tatiana Rosado ^{[1, 5]}

Affiliation

^[1] Univ Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[2] Santa Casa Sao Paulo Sch Med Sci, Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Sao Paulo - Brazil

^[4] Fac Israelita Ciencias Saude Albert Einstein, Sao Paulo - Brazil

^[5] Univ Birmingham, Inst Canc & Genom Sci, Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands - England

• Document type: Journal article
• Source: Molecular Neurobiology; v. 58, n. 7, p. 3015-3030, JUL 2021.
• Web of Science Citations: 1

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. (AU)

• FAPESP's process: 16/12039-7 - Lysine(K)-deacetylases modulation and its role in mitochondrial metabolism, dynamics and degradation: possible neuroprotection for amyotrophic lateral sclerosis
• Grantee: Mariana Dutra Brito
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 15/02041-1 - The role of lysine(K)-deacetylases on mitochondrial disorders's neuroprotection: perspectives of epigenetic therapy for amyotrophic lateral sclerosis and schizophrenia
• Grantee: Tatiana Rosado Rosenstock
• Support Opportunities: Research Grants - Young Investigators Grants