DNA methylation investigation in first episode of psychosis and in rats undergoing isolation rearing from weaning in the two major excitatory and inhibitory systems

• Grant number: 17/00624-5
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): May 10, 2017
• Effective date (End): May 09, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal researcher: Cristina Marta Del-Ben
• Grantee: Helene Aparecida Fachim
• Supervisor abroad: Gavin Paul Reynolds
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Sheffield Hallam University, England
• Associated to the scholarship: 15/02948-7 - Study of epigenetic alterations in GABAergic neurotransmission in schizophrenia and other psychoses and in animals undergoing social isolation from weaning, BP.PD

Abstract

Schizophrenia is characterized by disturbances originate in neuronal development and a subtle brain pathology in which deficits in specific GABAergic and glutamatergic neuronal subtypes are apparent. This is demonstrated by decreases in markers of GABAergic neuronal functions, such as expression of the synthesising enzyme glutamic acid decarboxylase (GAD) and parvalbumin (PV), a protein present in a subgroup of GABA-containing interneurons; and also in the glutamatergic dysfunction, mainly N-methyl D- aspartate receptors (NMDARs). Several animal paradigms, such as isolation rearing, sub-chronic PCP administration and neonatal inflammatory challenge, that model aspects of schizophrenia also result in deficits of PV and GAD67, indicative of GABAergic pathology underlying the abnormal behaviours in these models. In parallel, knockout and knockdown animals for NMDAR subunits, such as NR1 and NR2, exhibit behavioural changes similar those present in schizophrenia. Recent studies have demonstrated abnormalities in DNA methylation in various indicators of GABAergic and glutamatergic function in schizophrenia. These abnormalities include both indicators of a general hypermethylation in brain regions important in the pathology of the disease, and effects on specific components principally linked to GABAergic and glutamatergic neurons. These findings suggest that a hyperfunctional DNA methylation may be responsible for deficiencies in excitatory and inhibitory neurotransmissions. There is also evidence suggesting that such effects may be ameliorated by antipsychotic drug treatment. As yet, however, these effects have not been investigated in the animal models that mimic aspects of schizophrenia and in patients in first episode of psychosis. Thus, the aim of this work is to evaluate if there is a hypermethylation in the GABAergic and glutamatergic markers in brain tissue and peripheral blood from rats undergoing isolation rearing and in the peripheral blood of patients in first episode of psychosis, siblings and health controls.

Scientific publications

(8)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FACHIM, HELENE A.; CORSI-ZUELLI, FABIANA; LOUREIRO, CAMILA M.; IAMJAN, SRI-ARUN; SHUHAMA, ROSANA; JOCA, SAMIA; MENEZES, PAULO ROSSI; HEALD, ADRIAN; LOUZADA-JUNIOR, PAULO; DALTON, CAROLINE F.; DEL-BEN, CRISTINA MARTA; REYNOLDS, GAVIN P. Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 108, JUN 8 2021. Web of Science Citations: 1.

LOUREIRO, CAMILA M.; FACHIM, HELENE A.; CORSI-ZUELLI, FABIANA; SHUHAMA, ROSANA; MENEZES, PAULO R.; DALTON, CAROLINE F.; DEL-BEN, CRISTINA M.; REYNOLDS, GAVIN P.; LOUZADA-JUNIOR, PAULO. The relationship of childhood trauma and DNA methylation of NMDA receptor genes in first-episode schizophrenia. Epigenomics, v. 13, n. 12, p. 927-937, JUN 2021. Web of Science Citations: 0.

LOUREIRO, CAMILA MARCELINO; CORSI-ZUELLI, FABIANA; FACHIM, HELENE APARECIDA; SHUHAMA, ROSANA; DE SOUZA CHAGAS, NATALIA MOTA; MENEZES, PAULO ROSSI; DEL-BEN, CRISTINA MARTA; LOUZADA-JUNIOR, PAULO. Plasma prevalence of anti-N-methyl-d-aspartate receptor IgG antibodies in early stages of psychosis. Ciênc. saúde coletiva, v. 26, n. 3, p. 1085-1094, MAR 2021. Web of Science Citations: 0.

CAMILA MARCELINO LOUREIRO; FABIANA CORSI-ZUELLI; HELENE APARECIDA FACHIM; ROSANA SHUHAMA; NATÁLIA MOTA DE SOUZA CHAGAS; PAULO ROSSI MENEZES; CRISTINA MARTA DEL-BEN; PAULO LOUZADA-JUNIOR. Plasma prevalence of anti-N-methyl-d-aspartate receptor IgG antibodies in early stages of psychosis. Ciênc. saúde coletiva, v. 26, n. 3, p. 1085-1094, 2021.

LOUREIRO, CAMILA MARCELINO; DA ROZA, DAIANE LEITE; CORSI-ZUELLI, FABIANA; SHUHAMA, ROSANA; FACHIM, HELENE APARECIDA; SIMOES-AMBROSIO, LIVIA MARIA CORDEIRO; DEMINICE, RAFAEL; JORDAO, ALCEU AFONSO; MENEZES, PAULO ROSSI; DEL-BEN, CRISTINA MARTA; LOUZADA-JUNIOR, PAULO. Plasma amino acids profile in first-episode psychosis, unaffected siblings and community-based controls. SCIENTIFIC REPORTS, v. 10, n. 1 DEC 8 2020. Web of Science Citations: 0.

LOUREIRO, CAMILA MARCELINO; FACHIM, HELENE APARECIDA; CORSI-ZUELLI, FABIANA; SHUHAMA, ROSANA; JOCA, SAMIA; MENEZES, PAULO ROSSI; DALTON, CAROLINE F.; DEL-BEN, CRISTINA MARTA; LOUZADA-JUNIOR, PAULO; REYNOLDS, GAVIN P. Epigenetic-mediated N-methyl-D-aspartate receptor changes in the brain of isolated reared rats. Epigenomics, v. 12, n. 22 NOV 2020. Web of Science Citations: 0.

CORSI-ZUELLI, FABIANA; FACHIM, HELENE APARECIDA; LOUREIRO, CAMILA MARCELINO; SHUHAMA, ROSANA; BERTOZI, GIULIANO; JOCA, SAMIA REGIANE LOURENGO; MENEZES, PAULO ROSSI; LOUZADA-JUNIOR, PAULO; DEL-BEN, CRISTINA MARTA. Prolonged Periods of Social Isolation From Weaning Reduce the Anti-inflammatory Cytokine IL-10 in Blood and Brain. FRONTIERS IN NEUROSCIENCE, v. 12, JAN 11 2019. Web of Science Citations: 1.

FACHIM, HELENE A.; SRISAWAT, UMARAT; DALTON, CAROLINE F.; REYNOLDS, GAVIN P. Parvalbumin promoter hypermethylation in postmortem brain in schizophrenia. Epigenomics, v. 10, n. 5, p. 519-524, MAY 2018. Web of Science Citations: 5.