Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice

Department of Physiology and Pharmacology, University of Rome "Sapienza", Piazzale Aldo Moro 5, 00185 Rome, Italy.
Neuropharmacology (Impact Factor: 5.11). 04/2012; 68. DOI: 10.1016/j.neuropharm.2012.04.013
Source: PubMed


Human studies suggest that a variety of prenatal stressors are related to high risk for cognitive and behavioral abnormalities associated with psychiatric illness (Markham and Koenig, 2011). Recently, a downregulation in the expression of GABAergic genes (i.e., glutamic acid decarboxylase 67 and reelin) associated with DNA methyltransferase (DNMT) overexpression in GABAergic neurons has been regarded as a characteristic phenotypic component of the neuropathology of psychotic disorders (Guidotti et al., 2011). Here, we characterized mice exposed to prenatal restraint stress (PRS) in order to study neurochemical and behavioral abnormalities related to development of schizophrenia in the adult. Offspring born from non-stressed mothers (control mice) showed high levels of DNMT1 and 3a mRNA expression in the frontal cortex at birth, but these levels progressively decreased at post-natal days (PND) 7, 14, and 60. Offspring born from stressed mothers (PRS mice) showed increased levels of DNMTs compared to controls at all time-points studied including at birth and at PND 60. Using GAD67-GFP transgenic mice, we established that, in both control and PRS mice, high levels of DNMT1 and 3a were preferentially expressed in GABAergic neurons of frontal cortex and hippocampus. Importantly, the overexpression of DNMT in GABAergic neurons was associated with a decrease in reelin and GAD67 expression in PRS mice in early and adult life. PRS mice also showed an increased binding of DNMT1 and MeCP2, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine in specific CpG-rich regions of the reelin and GAD67 promoters. Thus, the epigenetic changes in PRS mice are similar to changes observed in the post-mortem brains of psychiatric patients. Behaviorally, adult PRS mice showed hyperactivity and deficits in social interaction, prepulse inhibition, and fear conditioning that were corrected by administration of valproic acid (a histone deacetylase inhibitor) or clozapine (an atypical antipsychotic with DNA-demethylation activity). Taken together, these data show that prenatal stress in mice induces abnormalities in the DNA methylation network and in behaviors indicative of a schizophrenia-like phenotype. Thus, PRS mice may be a valid model for the investigation of new drugs for schizophrenia treatment targeting DNA methylation. This article is part of a Special Issue entitled 'Neurodevelopment Disorder'.

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Available from: Dennis Robert Grayson, Feb 12, 2014
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    • "In one study where offspring sex was not specified, prenatal restraint stress in rats increased DNMT1 mRNA in the cerebral cortex of adult offspring [52]. In other studies, prenatal restraint stress in male Swiss-albino mice increased DNMT1 mRNA and protein in the frontal cortex [53] [54]. These latter findings contradict our results showing that PNS had no significant effect on DNMT1 protein in adult male C57BL/6 offspring. "
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    ABSTRACT: Stress during pregnancy has a wide variety of negative effects in both human [1] and animal offspring [2]. These effects are especially apparent in various forms of learning and memory such as object recognition [3] and spatial memory [4]. The cognitive effects of prenatal stress (PNS) may be mediated through epigenetic changes such as histone acetylation and DNA methylation [5]. As such, the present study investigated the effects of chronic unpredictable PNS on memory and epigenetic measures in adult offspring. Mice that underwent PNS exhibited impaired spatial memory in the Morris water maze, as well as sex-specific changes in levels of DNA methyltransferase (DNMT) 1 protein, and acetylated histone H3 (AcH3) in the hippocampus, and serum corticosterone. Male mice exposed to PNS exhibited decreased hippocampal AcH3, whereas female PNS mice displayed a further reduction in AcH3, as well as heightened hippocampal DNMT1 protein levels and corticosterone levels. These data suggest that PNS may epigenetically reduce transcription in the hippocampus, particularly in females in whom this effect may be related to increased baseline stress hormone levels, and which may underlie the sexual dimorphism in rates of mental illness in humans. Copyright © 2014. Published by Elsevier B.V.
    Behavioural Brain Research 12/2014; 281. DOI:10.1016/j.bbr.2014.12.001 · 3.03 Impact Factor
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    • "These mice show a suite of behavioral abnormalities including reduced social interaction and impaired fear conditioning suggestive of a vulnerable phenotype. These defects were reversed by treatment with the histone deacetylase (HDAC) inhibitor valproate or the atypical antipsychotic clozapine [49]. Neonatal handling can also reduce the longterm negative consequences of prenatal stress [50]. "
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    Epigenetics in Psychiatry, 1st edited by Peedicayil, Grayson, Avramopoulos, 07/2014: pages 325-342; Academic Press., ISBN: 978-0-12-417115-5
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    • "Valproate is a pharmacoepigenomic agent that has epigenetic effects on the modification of GABAergic interneurons (Csoka and Szyf, 2009). Valproate has been reported to ameliorate cognitive impairments in adult mice via demethylation of GABAergic-promotors (Tremolizzo et al., 2002, 2005; Matrisciano et al., 2013), inhibition of histone deacetylases (Phiel et al., 2001), and enhancement of central GABAergic tone that is mediated through an inhibition of GABA-transaminase (Johannessen, 2000). The reciprocal interaction between defects of NRG1 and hypermethylation of GABAergic promotors remains unclear. "
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    ABSTRACT: Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.
    Frontiers in Behavioral Neuroscience 04/2014; 8:126. DOI:10.3389/fnbeh.2014.00126 · 3.27 Impact Factor
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