Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice

Tremolizzo, Lucio; Doueiri, Mohemed Salim; Dong, Erbao; Grayson, Dennis R.; Davis, John M.; Pinna, Graziano; Tueting, Patricia; Rodriguez-Menendez, Virginia; Costa, E.; Guidotti, Alessandro

doi:10.1016/j.biopsych.2004.11.046

Cited by 244 publications

(201 citation statements)

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“…As in previous studies (22,24,25), protracted daily MET treatments and the consequent RELN and GAD 67 promoter hypermethylation are associated with an Ϸ50% reduction of reelin and GAD 67 expression (Fig. 5).…”

Section: Resultssupporting

confidence: 82%

“…In fact, measurement of FC SAM 12 h after 7 days of MET treatment (22,24) showed only a slight increase of this methyl group donor. Furthermore, preliminary data suggest that expression of FC DNMT1, which is the most abundant form of DNMT mRNA expressed in the mouse brain, is not changed by the protracted MET treatment schedule adopted in our experiments.…”

Section: Discussionmentioning

confidence: 91%

“…We have also reported that the increase of SAM brain content elicited by protracted L-methionine (MET) treatment in mice causes the RELN and GAD 67 promoter hypermethylation that is probably operative in the transcriptional down-regulation of these genes in the FC and perhaps other brain areas of psychotic patients (19,(22)(23)(24)(25).…”

mentioning

confidence: 99%

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Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters

Dong

Guidotti

Grayson

et al. 2007

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

176

139

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Reelin and glutamic acid decarboxylase 67 (GAD67) expression down-regulation in GABAergic interneurons of mice exposed to protracted treatment with L-methionine (MET) is attributed to RELN and GAD 67 promoter cytosine-5-hypermethylation. This process recruits various transcription repressor proteins [methyl-CpG binding protein (MeCP2) and histone deacetylases (HDACs)] leading to formation of transcriptionally inactive chromatin. Here, we tested the hypothesis that RELN and GAD 67 promoter cytosine-5-hypermethylation induced by a protracted MET treatment is reversible and that repeated administration of HDAC inhibitors influences this process by an activation of DNA-cytosine-5-demethylation. In the frontal cortices of mice receiving MET (5.2 mmol/kg twice a day for 7 days) and killed at 1, 2, 3, 6, and 9 days during MET washout, we measured RELN (base pairs ؊414 to ؊242) and GAD 67 (base pairs ؊1133 to ؊942) promoter methylation and MeCP2 bound to methylated cytosines of RELN (base pairs ؊520 to ؊198) and GAD 67 (base pairs ؊446 to ؊760) promoters. Levels of RELN and GAD 67 promoter hypermethylation induced by 7 days of MET treatment declines by Ϸ50% after 6 days of MET withdrawal. When valproate (VPA) (2 mmol/kg) or MS-275 (0.015-0.12 mmol/ kg), two structurally unrelated HDAC inhibitors, was given after MET treatment termination, VPA and MS-275 dramatically accelerated RELN and GAD 67 promoter demethylation in 48 -72 h. At these doses, VPA and MS-275 effectively increased the binding of acetylhistone-3 to RELN and GAD 67 promoters, suggesting that histone-3 covalent modifications modulate DNA demethylation in terminally differentiated neurons, supporting the view that, directly or indirectly, HDAC inhibitors may facilitate DNA demethylation. DNA demethylation ͉ histone deacetylase inhibitors ͉ valproate ͉ MS-275T he down-regulation of glutamic acid decarboxylase 67 (GAD 67 ) and reelin expressed in telencephalic GABAergic neurons is a characteristic and prominent neuropathological alteration observed in patients with schizophrenia (SZ) and bipolar (BP) disorder with psychosis (1-8).GAD 67 is one of the two molecular forms of GABA-synthesizing enzymes and plays an important role in maintaining GABA steady-state levels at GABAergic synapses (9). Reelin is a 400-kDa glycoprotein synthesized by cortical GABAergic neurons. On secretion into the extracellular matrix, reelin adheres to dendritic shafts and spines of pyramidal neurons (10-12). Previous experiments have suggested that reelin may play a role in the regulation of event-related protein synthesis in dendritic spines (11). Reelin has also been implicated in synaptic plasticity and learning and memory functions (10-15).The down-regulation of reelin expression is probably responsible for the decrease in dendritic spine density observed in the frontal cortex (FC) of heterozygous reeler mice and perhaps also in the prefrontal cortex (PFC) of SZ and BP disorder patients (12). Hence, a deficit in GABAergic transmission because of a decrease of GAD 67 and reelin...

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 91%

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Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters

Dong

Guidotti

Grayson

et al. 2007

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

176

139

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“…193,194 Weaver and associates 195 demonstrated in rat pups that behaviorally programmed, persistent epigenomic alterations of a glucocorticoid receptor gene promoter in the hippocampus induced by certain styles of maternal behavior could be reversed by central infusion of an HDAC inhibitor. Tremolizzo and colleagues 196 found that hypermethylation of the reelin promoter and subsequent decrease of reelin expression, which have been suggested by recent studies to be present in BD and schizophrenia patients, were prevented by valproate in doses inhibitory to HDACs. Thus, HDAC inhibitors represent a class of agents that may be available for clinical trials in mood disorders (see Table 2) as well as a theoretical model by which other agents that target epigenetic regulation mechanisms potentially involved in mood disorder pathogenesis may be pursued.…”

Section: Valproate Histone Deacetylase and Epigenetic Regulation Ofmentioning

confidence: 92%

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Carlson¹,

Singh²,

Zarate³

et al. 2006

NeuroRX

136

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Summary:Major depressive disorder and bipolar disorder are severe mood disorders that affect the lives and functioning of millions each year. The majority of previous neurobiological research and standard pharmacotherapy regimens have approached these illnesses as purely neurochemical disorders, with particular focus on the monoaminergic neurotransmitter systems. Not altogether surprisingly, these treatments are inadequate for many individuals afflicted with these devastating illnesses. Recent advances in functional brain imaging have identified critical neural circuits involving the amygdala and other limbic structures, prefrontal cortical regions, thalamus, and basal ganglia that modulate emotional behavior and are disturbed in primary and secondary mood disorders. Growing evidence suggests that mechanisms of neural plasticity and cellular resilience, including impairments of neurotrophic signaling cascades as well as altered glutamatergic and glucocorticoid signaling, underlie the dysregulation in these circuits. The increasing ability to monitor and modulate activity in these circuits is beginning to yield greater insight into the neurobiological basis of mood disorders. Modulation of dysregulated activity in these affective circuits via pharmacological agents that enhance neuronal resilience and plasticity, and possibly via emerging nonpharmacologic, circuitry-based modalities (for example, deep brain stimulation, magnetic stimulation, or vagus nerve stimulation) offers promising targets for novel experimental therapeutics in the treatment of mood disorders.

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“…Further work has shown that, in normal mice, chronic L-methionine treatment can lead to reductions in social interaction and impaired social recognition. 312 Dong et al 313,314 have provided evidence that reduced expression of reelin and GAD67 in the L-methionine-exposed mouse may be mediated by increased binding of Mecp2 to reelin and GAD67 promotor regions, and that valproic acid interrupts this enhanced association with Mecp2. 315 The findings raise the question of whether the detrimental prenatal effects of valproic acid exposure may be linked to disruption of normal MECP2 action, with subsequent alterations in RELN and GAD67 expression and dysregulation of GABAergic function in cortical regions.…”

Section: Epigenetic Regulation and Autismmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice

Cited by 244 publications

References 50 publications

Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters

Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Advances in behavioral genetics: mouse models of autism

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