Epigenetic Modifications of GABAergic Interneurons Contribute to Deficits in Adult Hippocampus Neurogenesis and Depression-Like Behavior in Prenatally Stressed Mice

Abstract

Background Prenatal stress (PRS) is considered a risk factor for depressive disorder. Adult hippocampal neurogenesis is believed to play a role in the regulation of affective behaviors. GABAergic interneuron is a key modulator in adult hippocampal neurogenesis. Growing evidence indicates that PRS has adverse effects on adult hippocampal neurogenesis and DNA epigenetic modifications of the GABAergic system. The aim of this study was to investigate whether epigenetic GABAergic dysfunction participates in the negative impact of PRS on adult hippocampal neurogenesis and related emotional behaviors. Methods Behavioral tests were used to explore PRS-induced depression-like behaviors of adult female mice. Immunohistochemistry staining, real-time reverse transcription-polymerase chain reaction, western blot, and chromatin immunoprecipitation were employed to detect adult neurogenesis and epigenetic changes of the GABAergic system in the hippocampus of PRS mice. Results PRS mice developed a depression phenotype accompanied by the inhibited maturation of hippocampal newborn neurons. Compared with control mice, PRS mice showed decreased expression of glutamic acid decarboxylase 67 at the mRNA and protein levels. GABAA receptor agonist phenobarbital could rectify the decrease of 5-bromo-2-deoxyuridine/neuronal nuclei double-positive (BrdU+/NeuN+) cells in PRS mice. PRS mice also showed increased expression of DNA methyltransferase 1 and increased binding of DNA methyltransferase 1 to glutamic acid decarboxylase 67 promoter region. The treatment with DNA methyltransferase 1 inhibitor 5-aza-deoxycytidine restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in PRS mice via improving GABAergic system. Conclusions The present results indicate that epigenetic changes of the GABAergic system are responsible for adult hippocampus neurogenesis and depression-like behaviors in PRS mice.

Epigenetic Regulation of the Hippocampus, with Special Reference to Radiation Exposure

“…The generation of new neurons in the adult central nervous system (CNS) in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus is one of the major breakthroughs in neuroscience research. Adult hippocampal neurogenesis occurs in the DG and refers to the formation of new functional dentate granule cells from neural stem cells (NSCs) [ 10 ] contributing to learning and memory [ 11 ] and also mood regulation [ 54 ]. Adult hippocampal neurogenesis was first observed in rodents [ 55 ] and later confirmed in humans [ 56 , 57 , 58 ].…”

“…Due to this, adult hippocampal neurogenesis provides a means for both functional and structural plasticity in the hippocampus. Dysregulation of adult hippocampal neurogenesis has been shown to cause cognitive decline and psychological symptoms [ 10 ].…”

“…Mice with Gadd45b deletions showed deficits in the proliferation of neural progenitors and dendritic growth in the hippocampus [ 60 ]. In addition, mice exposed to prenatal stress showed increased expressions of DNA methyltransferase 1 (DNMT1), and also an increase in its binding to the glutamic acid decarboxylase 67 (GAD67) promoter, leading to an impairment in the genesis of the gamma-aminobutyric acid (GABA) interneurons, suggesting that prenatal upregulation of DNMT1 may reduce interneuron genesis [ 10 ]. On the other hand, the expression of DMNT1 in neural precursor cells was also shown to be crucial for the survival of newly generated neurons in the adult hippocampus.…”

“…GABAergic interneurons are key modulators of adult hippocampal neurogenesis. In prenatally-stressed mice, epigenetic modifications of GABAergic interneurons cause depression and also deficits in hippocampal neurogenesis [ 10 ] due to an increase in DNMT1 binding to the GAD67 promoter. Mice exposed to prenatal stress had higher levels of DNMT1 and DMNT3a as compared to controls, and this overexpression of DNMTs correlated with a decrease in reelin and GAD67 expression [ 115 ].…”

“…The production of reactive oxygen species (ROS), pro-inflammatory cytokines and chemokines, pro-apoptotic proteins, autophagosome markers, excitatory neurotransmitters and neurotrophic factors may be involved in hippocampal neuropathy and cognitive impairment [ 6 , 7 ]. Recent studies have suggested that epigenetic mechanisms are involved not only in normal hippocampal development and regulation [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], but also in radiation-induced hippocampal pathophysiological changes leading to the development of neurological and neuropsychological disorders [ 15 ]. In this paper, we briefly introduce major mechanisms of epigenetic regulation, followed by a review of the epigenetic regulation of hippocampal neurogenesis.…”