Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation

Fachim, Helene; Corsi-Zuelli, Fabiana; Loureiro, Camila Marcelino; Iamjan, Sri-arun; Shuhama, Rosana; Joca, Sâmia Regiane Lourenço; Menezes, Paulo Rossi; Heald, Adrian; Louzada‐Júnior, Paulo; Dalton, Caroline; Del-Ben, Cristina Marta; Reynolds, Gavin P.

doi:10.1016/j.pnpbp.2020.110188

Cited by 24 publications

(15 citation statements)

References 83 publications

(102 reference statements)

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“…BDNF encodes the brain-derived neurotrophic factor that contributes to the neuronal plasticity of the brain by regulating the activity of several neurotransmitter receptors, such as GABA and tyrosine kinase B (TrkB) receptors, and plays a crucial role in learning and memory formation [ 64 ]. Animal models have shown that early-life stressors, as well as chronic stress in adulthood, induce methylation of BDNF promoters I and IV leading to lower expression levels of BDNF in the hippocampus [ 65 , 66 ].…”

Section: Epigenetic Alterations As a Cause Of Dysregulation Of The Stress Responsementioning

confidence: 99%

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

Mourtzi

Sertedaki

Charmandari

2021

IJMS

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Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.

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Section: Epigenetic Alterations As a Cause Of Dysregulation Of The Stress Responsementioning

confidence: 99%

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

Mourtzi

Sertedaki

Charmandari

2021

IJMS

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“…Similarly, we previously found brain-derived neurotrophic factor (BDNF) methylation correlated with childhood trauma and equivalent changes in BDNF methylation identified in rats undergoing isolation rearing from weaning, yet those changes were also not correlated with behavioural alterations (Fachim et al, 2020). Although no direct correlation between behaviour (cognitive impairments) and alterations in the DNA methylation at promoter regions of Grin1 and Grin2b NMDAR subunits observed in scPCP-treated rats in this study has been found, both changes may indicate a possible glutamatergic dysfunction that probably affects synaptic plasticity in the PFC and hippocampus of scPCP animals and may be key to explaining the cognitive impairments in schizophrenia (Bubeníková-Valešová et al, 2008; Neill et al, 2010).…”

Section: Discussionmentioning

confidence: 83%

Subchronic PCP effects on DNA methylation and protein expression of NMDA receptor subunit genes in the prefrontal cortex and hippocampus of female rats

et al. 2022

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Background: N-methyl-d-aspartate receptor (NMDAR) dysfunction is implicated in schizophrenia, and NMDAR antagonists, such as phencyclidine (PCP), can induce behaviours that mimic aspects of the disorder. Aims: We investigated DNA methylation of Grin1, Grin2a and Grin2b promoter region and NR1 and NR2 protein expression in the prefrontal cortex (PFC) and hippocampus of adult female Lister-hooded rats following subchronic PCP (scPCP) administration. We also determined whether any alterations were tissue-specific. Methods: Rats were divided into two groups that received vehicle (0.9% saline) or 2 mg/kg PCP twice a day for 7 days (n = 10 per group). After behavioural testing (novel object recognition), to confirm a cognitive deficit, brains were dissected and NMDAR subunit DNA methylation and protein expression were analysed by pyrosequencing and ELISA. Line-1 methylation was determined as a measure of global methylation. Data were analysed using Student’s t-test and Pearson correlation. Results: The scPCP administration led to Grin1 and Grin2b hypermethylation and reduction in NR1 protein in both PFC and hippocampus. No significant differences were observed in Line-1 or Grin2a methylation and NR2 protein. Conclusions: The scPCP treatment resulted in increased DNA methylation at promoter sites of Grin1 and Grin2b NMDAR subunits in two brain areas implicated in schizophrenia, independent of any global change in DNA methylation, and are similar to our observations in a neurodevelopmental animal model of schizophrenia – social isolation rearing post-weaning. Moreover, these alterations may contribute to the changes in protein expression for NMDAR subunits demonstrating the potential importance of epigenetic mechanisms in schizophrenia.

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“…Afterwards, the DNA was bisulfite converted using EpiTec Fast DNA Bisulphite Kit (Qiagen) to convert unmethylated cytosine residues to uracil with a calculated mean conversion of 99%. A pyrosequencing method was used for the determination of methylation at four CpG sites within the BDNF IV exon, as previously described by our group [ 29 ]. The sequence was amplified by PCR, using the primers described on Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Methylation Status of Exon IV of the Brain-Derived Neurotrophic Factor (BDNF)-Encoding Gene in Patients with Non-Diabetic Hyperglycaemia (NDH) before and after a Lifestyle Intervention

et al. 2022

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BDNF signalling in hypothalamic neuronal circuits is thought to regulate mammalian food intake. In light of this, we investigated how a lifestyle intervention influenced serum levels and DNA methylation of BDNF gene in fat tissue and buffy coat of NDH individuals. In total, 20 participants underwent anthropometric measurements/fasting blood tests and adipose tissue biopsy pre-/post-lifestyle (6 months) intervention. DNA was extracted from adipose tissue and buffy coat, bisulphite converted, and pyrosequencing was used to determine methylation levels in exon IV of the BDNF gene. RNA was extracted from buffy coat for gene expression analysis and serum BDNF levels were measured by ELISA. No differences were found in BDNF serum levels, but buffy coat mean BDNF gene methylation decreased post-intervention. There were correlations between BDNF serum levels and/or methylation and cardiometabolic markers. (i) Pre-intervention: for BDNF methylation, we found positive correlations between mean methylation in fat tissue and waist-hip ratio, and negative correlations between mean methylation in buffy coat and weight. (ii) Post-intervention: we found correlations between BDNF mean methylation in buffy coat and HbA1c, BDNF methylation in buffy coat and circulating IGFBP-2, and BDNF serum and insulin. Higher BDNF % methylation levels are known to reduce BNDF expression. The fall in buffy coat mean BDNF methylation plus the association between lower BDNF methylation (so potentially higher BDNF) and higher HbA1c and serum IGFBP-2 (as a marker of insulin sensitivity) and between lower serum BDNF and higher circulating insulin are evidence for the degree of BDNF gene methylation being implicated in insulinisation and glucose homeostasis, particularly after lifestyle change in NDH individuals.

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Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation

Cited by 24 publications

References 83 publications

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

Subchronic PCP effects on DNA methylation and protein expression of NMDA receptor subunit genes in the prefrontal cortex and hippocampus of female rats

Methylation Status of Exon IV of the Brain-Derived Neurotrophic Factor (BDNF)-Encoding Gene in Patients with Non-Diabetic Hyperglycaemia (NDH) before and after a Lifestyle Intervention

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