Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects

Author(s)

Sales, Amanda J. ^{[1, 2]} ; Maciel, Izaque S. ^[1] ; Suavinha, Angelica C. D. R. ^[3] ; Joca, Samia R. L. ^{[4, 3, 5]}

Affiliation

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, Ribeirao Preto, SP - Brazil

^[2] FMRP USP, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Biomol Sci, Ribeirao Preto, SP - Brazil

^[4] Aarhus Univ, Dept Clin Med, Translat Neuropsychiat Unit, Aarhus - Denmark

^[5] FCFRP USP, Av Cafe SN, BR-14040903 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Molecular Neurobiology; v. 58, n. 2, p. 777-794, FEB 2021.
• Web of Science Citations: 1

Abstract

Background Stress increases DNA methylation, primarily a suppressive epigenetic mechanism catalyzed by DNA methyltransferases (DNMT), and decreases the expression of genes involved in neuronal plasticity and mood regulation. Despite chronic antidepressant treatment decreases stress-induced DNA methylation, it is not known whether inhibition of DNMT would convey rapid antidepressant-like effects. Aim This work tested such a hypothesis and evaluated whether a behavioral effect induced by DNMT inhibitors (DNMTi) corresponds with changes in DNA methylation and transcript levels in genes consistently associated with the neurobiology of depression and synaptic plasticity (BDNF, TrkB, 5-HT1A, NMDA, and AMPA). Methods MaleWistarrats received intraperitoneal (i.p.) injection of two pharmacologically different DNMTi (5-AzaD 0.2 and 0.6 mg/kg or RG108 0.6 mg/kg) or vehicle (1 ml/kg), 1 h or 7 days before the learned helplessness test (LH). DNA methylation in target genes and the correspondent transcript levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC) using meDIP-qPCR. In parallel separate groups, the antidepressant-like effect of 5-AzaD and RG108 was investigated in the forced swimming test (FST). The involvement of cortical BDNF-TrkB-mTOR pathways was assessed by intra-ventral medial PFC (vmPFC) injections of rapamycin (mTOR inhibitor), K252a (TrkB receptor antagonist), or vehicle (0.2 mu l/side). Results We found that both 5-AzaD and RG108 acutely and 7 days before the test decreased escape failures in the LH. LH stress increased DNA methylation and decreased transcript levels of BDNF IV and TrkB in the PFC, effects that were not significantly attenuated by RG108 treatment. The systemic administration of 5-AzaD (0.2 mg/kg) and RG108 (0.2 mg/kg) induced an antidepressant-like effect in FST, which was, however, attenuated by TrkB and mTOR inhibition into the vmPFC. Conclusion These findings suggest that acute inhibition of stress-induced DNA methylation promotes rapid and sustained antidepressant effects associated with increased BDNF-TrkB-mTOR signaling in the PFC. (AU)

• FAPESP's process: 12/17626-7 - Cellular and molecular mechanisms involved in the role of atypical neurotransmitters in neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/01955-0 - Effect of inhibitors of DNMTs and antidepressants on DNA methylation in candidate genes involved in the neurobiology of depression
• Grantee: Amanda Juliana Sales
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/17281-7 - Involvement of epigenetic mechanisms induced by DNA methylation on stress-induced behavioral consequences and on the expression of genes involved in the neurobiology of depression
• Grantee: Sâmia Regiane Lourenço Joca
• Support Opportunities: Regular Research Grants