Involvement of Epigenetic Modifications of GABAergic Interneurons in Basolateral Amygdala in Anxiety-like Phenotype of Prenatally Stressed Mice

Abstract

BackgroundPrenatal stress is considered a risk factor for anxiety disorder. Downregulation in the expression of GABAergic gene, that is, glutamic acid decarboxylase 67, associated with DNA methyltransferase overexpression in GABAergic neurons has been regarded as a characteristic component of anxiety disorder. Prenatal stress has an adverse effect on the development of the basolateral amygdala, which is a key region in anxiety regulation. The aim of this study is to analyze the possibility of epigenetic alterations of GABAergic neurons in the basolateral amygdala participating in prenatal stress-induced anxiety.MethodsBehavioral tests were used to explore the prenatal stress-induced anxiety behaviors of female adult mice. Real-time RT-PCR, western blot, chromatin immunoprecipitation, and electrophysiological analysis were employed to detect epigenetic changes of GABAergic system in the basolateral amygdala.ResultsPrenatal stress mice developed an anxiety-like phenotype accompanied by a significant increase of DNA methyltransferase 1 and a reduced expression of glutamic acid decarboxylase 67 in the basolateral amygdala. Prenatal stress mice also showed the increased binding of DNA methyltransferase 1 and methyl CpG binding protein 2 to glutamic acid decarboxylase 67 promoter region. The decrease of glutamic acid decarboxylase 67 transcript was paralleled by an enrichment of 5-methylcytosine in glutamic acid decarboxylase 67 promoter regions. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-basolateral amygdala synaptic transmission of prenatal stress mice. 5-Aza-deoxycytidine treatment restored the increased synaptic transmission and anxiety-like behaviors in prenatal stress mice via improving GABAergic system.ConclusionThe above results suggest that DNA epigenetic modifications of GABAergic interneurons in the basolateral amygdala participate in the etiology of anxiety-like phenotype in prenatal stress mice.

Enrichment of genomic pathways based on differential DNA methylation profiles associated with chronic musculoskeletal pain in older adults: An exploratory study

“… 41 DNA epigenetic modifications of amygdala GABAergic interneurons were involved in anxiety-like behaviors that were reversed with a demethylating agent. 42 In our own participants with chronic pain, GABA concentrations in the frontal cortex are significantly reduced compared to no-pain controls. 43 Interestingly, GABA has immunoinhibitory effects on T-cells, 44 – 46 and GABA A receptors mediate inhibition of T cell responses.…”

Enrichment of Genomic Pathways Based on Differential DNA Methylation Associated With Chronic Postsurgical Pain and Anxiety in Children: A Prospective, Pilot Study

“…[33] DNA epigenetic modifications of GABAergic interneurons in the basolateral amygdala were shown to be involved in the anxiety-like phenotypes in prenatal stress mice, and importantly, this was shown to be reversible with a demethylating agent, 5-Aza deoxycytidine. [79] Further, our functional genomics analysis show that many of the CpG sites identified are located in regions of the brain marked by lysine 27 tri-methylation (H3K27me3), which is known to negatively regulate gene expression. Our study thus provides new evidence for DNA methylation as a mechanism for possibly reduced function of the GABA receptor pathway genes and its role in CPSP and anxiety pathogenesis.…”

<p>The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders</p>

“…Changes in DNA methylation and histone modifications in animal models of ADs are listed in Table 1 and in peripheral cells in patients with ADs in Table 2. It is interesting that in two studies 24,25 hypermethylation of the GAD1 gene, which encodes the enzyme glutamic acid decarbox-ylase1, the enzyme that catalyzes the decarboxylation of glutamic acid to GABA, was found. Hypermethylation of DNA correlates with inhibition of gene expression.…”

“…13 Hence hypermethylation of GAD1 would lead to reduced expression of GAD1, and hence reduced formation of GABA, the major inhibitory neurotransmitter in the brain. In this context, it is known that patients with PD have been found to have lower brain concentrations of Rat basolateral amygdala Hypermethylation in GAD1 gene [24] Mouse basolateral amygdal Hypermethylation of GAD1 gene [25]…”