Part I. Biochemical Studies

Wyatt, Richard Jed; Termini, Benedict A.; Davis, John L.

doi:10.1093/schbul/1.4.10

Cited by 75 publications

(8 citation statements)

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“…37). We have previously reported (38,39) that the protracted administration to mice of large doses of MET generates behavioral endophenotypes reminiscent of the psychosis recrudescence induced by MET in SZP.…”

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Reelin and glutamic acid decarboxylase ₆₇ promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

Dong

Agís‐Balboa

Simonini

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

184

123

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Reduction of prefrontal cortex glutamic acid decarboxylase (GAD 67) and reelin (mRNAs and proteins) expression is the most consistent finding reported by several studies of postmortem schizophrenia (SZ) brains. Converging evidence suggests that the reduced GAD 67 and reelin expression in cortical GABAergic interneurons of SZ brains is the consequence of an epigenetic hypermethylation of RELN and GAD 67 promoters very likely mediated by the overexpression of DNA methyltransferase 1 in cortical GABAergic interneurons. Studies of the molecular mechanisms (DNA methylation plus related chromatin remodeling factors) that cause the down-regulation of reelin and GAD 67 in SZ brains have important implications not only to understand the disease pathogenesis but also to improve present pharmacological interventions to treat SZ. The mouse treated with L-methionine models some of the molecular neuropathologies detected in SZ, including the hypermethylation of RELN promoter CpG islands and the down-regulation of reelin and GAD 67 expression. We now report that in these mice, RELN and GAD 67 promoters express an increased recruitment of methyl-CpG binding domain proteins. In these mice the histone deacetylase inhibitor valproate, which increases acetylated histone content in cortical GABAergic interneurons, also prevents METinduced RELN promoter hypermethylation and reduces the methylCpG binding domain protein binding to RELN and GAD 67 promoters. These findings suggest that DNA hypermethylation and the associated chromatin remodeling may be critically important in mediating the epigenetic down-regulation of reelin and GAD 67 expression detected in cortical GABAergic interneurons of SZ patients.DNA methyltransferase1 ͉ L-methionine ͉ methyl binding domain proteins ͉ valproate ͉ chromatin S chizophrenia (SZ) pathophysiology is characterized by a down-regulation of several GABAergic neuronal markers including GAD 67 and reelin mRNAs and proteins (1-8).Reelin is an extracellular matrix protein, synthesized and secreted from cortical GABAergic interneurons (9-12), that surrounds apical and basal dendritic spines of pyramidal cortical neurons (13-14). This protein not only plays a defined role in prenatal central nervous system development (13-15) but also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation (14,16,17). Very likely, reelin has a role in regulating the event-related increase of protein synthesis mediated by the dendritic translation of cytosolic mRNAs (18). In this scenario, the down-regulation of reelin expression in neocortices and hippocampi of SZ patients (SZP) (1, 5, 19) may be important in mediating the down-regulation of pyramidal neuron dendritic branching and spine expression and in the neuropil hypoplasticity typical of SZ (20)(21)(22).GAD 67 is one of two molecular forms of the GABA synthesizing enzymes expressed in GABAergic interneurons (23). In SZP, the down-regula...

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confidence: 99%

Reelin and glutamic acid decarboxylase ₆₇ promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

Dong

Agís‐Balboa

Simonini

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

184

123

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“…In looking for an approach to induce promoter CpG-island hypermethylation in mice, we were attracted by several reports on the aggravation of schizophrenia symptoms elicited by a 2-week treatment of these patients with high daily doses (20-40 g) of L-methionine (13). Between 1961 and 1971, 10 studies were published evaluating whether a treatment with L-methionine, a precursor in the biosynthesis of S-adenosyl-methionine (SAM), mitigated any of the symptoms of schizophrenia (for a review see ref.…”

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“…Between 1961 and 1971, 10 studies were published evaluating whether a treatment with L-methionine, a precursor in the biosynthesis of S-adenosyl-methionine (SAM), mitigated any of the symptoms of schizophrenia (for a review see ref. 13). It was disappointing that every one of the 10 studies reported that L-methionine exacerbates the symptoms of schizophrenia (13).…”

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confidence: 99%

“…13). It was disappointing that every one of the 10 studies reported that L-methionine exacerbates the symptoms of schizophrenia (13). Interestingly, the study by Antun et al (14) excluded that Lmethionine caused a ''chronic brain syndrome'' or other forms of neurotoxicity, theoretically linking the increased brain methylation to the exacerbation of schizophrenia symptoms.…”

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“…Therefore we tested whether by increasing brain SAM content with L-methionine we could decrease the expression of brain GAD 67 and reelin mRNAs and proteins by changing the number of 5-methylcytosines in the CpG islands surrounding the promoters of these genes. In WT mice (WTM) treated with L-methionine we did not expect to observe significant behavioral changes, because in nonpsychiatric patients L-methionine treatment was asymptomatic (13). Thus, the experiments with methionine included HRM, in addition to the WTM, because these reelin-haploinsufficient mice exhibit molecular, neuroanatomical, and behavioral changes reminiscent of those found in schizophrenia (refs.…”

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An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

Tremolizzo

Carboni

Ruzicka

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

349

249

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Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical ␥-aminobutyric acid-ergic interneurons are downregulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this downregulation. Protracted L-methionine (6.6 mmol͞kg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD 67 mRNAs in both WT and heterozygous reeler mice. This effect of L-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of L-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulse͞startle interval increased in mice receiving L-methionine. Valproic acid (2 mmol͞kg for 15 days, twice a day) reverted L-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk. S tudies of heterozygous reeler mice (HRM) have provided preliminary evidence of a relationship between reelin haploinsufficiency, the decrease of dendritic spine expression density in frontal cortex (FC) pyramidal neurons and associated neuropil hypoplasticity, the down-regulation of glutamic acid decarboxylase (GAD) 67 expression, and the decrease in ␥-aminobutyric acid (GABA) turnover (1-3). Similar neurochemical and structural abnormalities were detected in the FC of schizophrenia postmortem brains (4-9). Hence, HRM may be a model to evaluate the efficacy of novel treatments for schizophrenia by monitoring drug actions on (i) reelin and GAD 67 mRNA expression, (ii) GABA turnover, and (iii) cortical neuropil plasticity including dendritic spine expression.The HRM model several aspects of the molecular neuropathology expressed in schizophrenia, although the mechanisms operative in these pathologies may be different. In fact, demographic studies of schizophrenia inheritance in identical twins show a concordance of Ϸ50%, which supports an epigenetic model but not gene haploinsufficiency of Mendelian origin. Investigation of a putative epigenetic mechanism attending schizophrenia vulnerability may therefore be in order (10). Along this line of thinking we have hypothesiz...

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Biological Psychiatry

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Part I. Biochemical Studies

Cited by 75 publications

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Reelin and glutamic acid decarboxylase ₆₇ promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

Reelin and glutamic acid decarboxylase ₆₇ promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

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Part I. Biochemical Studies

Cited by 75 publications

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Reelin and glutamic acid decarboxylase 67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

Reelin and glutamic acid decarboxylase 67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

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Reelin and glutamic acid decarboxylase ₆₇ promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

Reelin and glutamic acid decarboxylase ₆₇ promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia