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Updated December 2012

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An Epigenetic Hypothesis for Schizophrenia Pathophysiology
By Dennis R. Grayson, Alessandro Guidotti, and Erminio Costa


Dennis R. Grayson, Alessandro Guidotti, and Erminio Costa

Schizophrenia (Sz) is a devastating disorder of brain function with a population-wide morbidity approaching 1 percent. The genetics of this disease are perhaps the most studied facet of this disorder, but the emphasis on linkage and association analyses across the entire genome have provided only limited insight to explain the underlying etiological factors of the disease (Harrison and Weinberger, 2005). Genetic research has been hindered by, among other factors, the non-Mendelian inheritance of Sz, phenotypic heterogeneity, and a lack of disease-specific biomarkers. As of January 2008, the Schizophrenia Research Forum's SchizophreniaGene database showed that of the over 1,200 genetic studies performed thus far, significant summary odds have been obtained for several loci, including methyl tetrahydrofolate reductase (MTHFR), dopamine receptor D2, dopamine receptor D4, various NMDA selective glutamate receptors (NR2A, GRIN2A), and the serotonin transporter A4 (SLC6A4). Dysbindin and neuregulin have also shown positive association in some studies. However, while linkage and association studies are informative, several problems associated with the interpretation of complex genetics of Sz make their interpretation difficult. In fact, the inconsistencies associated with the results of recent meta-analyses of genome-wide scans and large sib-pair studies indicate that there is no replicable support for any of the currently considered candidate genes (Crow, 2007).

Recent thinking suggests that the origins of this disease may not lie strictly in DNA sequence variations; rather, these may be coupled with epigenetic dysfunctions as the key etiopathogenic factors (Petronis, 2004; Costa et al., 2006). An important series of studies that took place in the 1960s and 1970s, together with new data obtained from postmortem human tissue from schizophrenia patients and non-psychiatric subjects, has led us to suggest a novel hypothesis regarding the origins of this mental illness (see Costa et al., 2002). The proposed mechanism, which is a modification of the GABAergic hypothesis (see Guidotti et al., 2005; Lewis et al., 2005), states that aberrant gene expression (of, e.g., reelin, glutamic acid decarboxylase I [GAD1 or GAD67], vesicular GABA transporter [VGAT], GABA transporter [GAT-1], NMDA receptors [NR2s], and others [see Benes et al., 2007; Huang et al., 2007]) observed in GABAergic neurons of Sz patients is a consequence of promoter hypermethylation mediated by the overexpression of DNA methyltransferase I (and possibly other Dnmts). As proposed, the methylation hypothesis is somewhat narrow; however, we would like to include additional mechanisms consistent with altered epigenetic regulation of key promoters expressed in GABAergic neurons (Costa et al., 2007). These additional epigenetic modifications to specific promoters include, but are not limited to, altered DNA methylation and chromatin remodeling (Duman and Newton, 2007; Tsankova et al., 2007) through histone modifications including methylation (Huang et al., 2007) and other changes that induce a repressive chromatin state. We presume that each leads to the downregulation of the corresponding mRNAs as a consequence of promoter silencing, which collectively contributes to the symptoms observed in psychotic patients. Alternatively, it may be that promoter hypermethylation leads to secondary effects that impact on GABA function indirectly. For example, neuregulin has been shown to positively regulate NMDA receptors (Gu et al., 2005), which in turn can modulate the amount of GABA released at GABAergic synapses (Beneyto and Meador-Woodruff, 2007; Homayoun and Moghaddam, 2007). Hence, a downregulation of neuregulin could lead to NMDA receptor hypofunction, which would exacerbate the GABAergic hypofunction mediated by reduced levels of GAD1. Collectively, each of these possibilities needs to be explored in the context of the present hypothesis so as to better understand the relationships reported by different investigators. At the same time, a consideration of the epigenetic hypothesis may allow for reconciling many of the disparate findings that have thus far confused the field.

A link between methionine and psychosis
The epigenetic hypothesis is, in part, predicated on results from a series of clinical studies that were carried out in the late 1960s and were designed to improve the treatment of Sz patients (Park et al., 1965; Antun et al., 1971; reviewed in Costa et al., 2002). The experiment was based on the premise that because haloperidol was able to block dopamine receptors, then a decrease in brain dopamine levels should also prove beneficial. To this end, Sz patients and non-psychiatric subjects were treated with high doses of methionine (Met). Met was expected to increase the activity of enzymes that metabolize dopamine through methylation and to reduce dopamine levels in the brain. It was anticipated that the net effect would be to improve or alleviate the symptoms of patients receiving the amino acid. Instead, Met was found to elicit acute psychotic episodes if these patients had been previously symptomatic for Sz (Antun et al., 1971; Costa et al., 2002). Initially, it was thought that the Met induced the formation of a dopamine metabolite capable of initiating a psychotic episode. However, the levels of various dopamine metabolites remained largely unchanged. The mechanism for this Met-induced recrudescence of psychotic symptoms remained elusive until our laboratories were able to recapitulate this paradigm in the mouse. We were able to show that Met mediates changes in gene expression and promoter methylation in mice, both in vivo and in vitro (Tremolizzo et al., 2005; Noh et al., 2005; Dong et al., 2005; 2007). Interestingly, Met was shown to increase brain S-adenosylmethionine levels, and this increase coincided with changes in promoter methylation and changes in gene expression. In addition, we observed that there was an increased binding of methyl CpG binding proteins, such as MeCP2, to these promoters (Dong et al., 2007; Kundakovic et al., 2007). It is worth noting that prefrontal cortical levels of S-adenosylmethionine (SAM) are increased nearly twofold in patients with Sz (Guidotti et al., 2007), which is consistent with the hypothesis that abnormal methylation is associated with this disease. Some of the Met clinical studies were published decades ago, but it was not until our recent revival of these findings, coupled with our examination of the epigenetic hypothesis, that these studies were linked to the current hypothesis (Costa et al., 2002).

Alterations in the expression of Dnmts (Dnmt1, 3a, and/or 3b) in GABAergic neurons of Sz patients could lead to global changes in genomic methylation, resulting in downregulation in the expression of large numbers of promoters. It seems that while Dnmt1, 3a, and 3b are expressed in postmitotic cells, only Dnmt1 is highly expressed in GABAergic neurons and not in pyramidal neurons (Veldic et al., 2004; 2005; 2007). Dnmt1 is overexpressed in GABAergic neurons of cortical layers I and II and in medium spiny neurons of the caudate and putamen of Sz patients (Veldic et al., 2007). No apparent changes in Dnmt3a or 3b expression have been detected in Sz or bipolar disorder patients. However, the precise neuronal localization of the corresponding mRNAs have not been studied in sufficient detail. The role of these proteins in postmitotic neurons is not entirely clear, and numerous studies have shown that each of these work together with methyl CpG binding proteins and histone deacetylases to effect their function (Van Emburgh and Robertson, in press). Consistent with the increased expression of Dnmt1 in cortical GABAergic neurons of Sz patients (Guidotti et al., 2005), we (Grayson et al., 2005) and others (Abdolmaleky et al., 2005) have shown that portions of the reelin promoter are hypermethylated in Sz patients. We propose that the reduced expression of the mRNAs encoding reelin, GAD1, and other mRNAs results in a decrease in GABAergic interneuron inhibitory tone (GABAergic hypofunction) that has been described in Sz patients and that appears to be linked to a disruption of pyramidal neuron firing rates (Benes and Berretta, 2001; Guidotti et al., 2005; Lewis et al., 2005, Levenson and Sweatt, 2005). This could explain many of the observations linking inappropriate inhibition of hyperexcitable auditory and visual circuits resulting in the perception of hallucinations (inappropriate sensory information) observed in patients suffering from psychosis. The relevant filtering circuits for extraneous sensory information processing are GABAergic and hence not likely to be functioning effectively (Loh et al., 2007).

Methylation and demethylation may act as neuronal gene expression switches
While the precise combinations of Dnmts (1, 3a, or 3b) active in specific neurons are not currently known (Veldic et al., 2004; Levenson et al., 2006), it seems clear that a role for methylation in normal brain function is emerging. For example, in some rats, maternal grooming behaviors alter the methylation status of the hippocampal glucocorticoid receptor gene in their offspring (Weaver et al., 2004; 2005; Meaney and Szyf, 2005). More recently, using contextual fear conditioning, changes in reelin and protein phosphatase I (PP1) promoter methylation have been linked to memory consolidation (Miller and Sweatt, 2007). Some researchers argue that methylation patterns in the context of chromatin remodeling might be reversible and also could be intimately linked to histone deacetylation. In fact, the histone deacetylase inhibitor valproic acid, which is commonly prescribed to psychotic patients as a mood stabilizer, is thought to act in part by increasing DNA demethylation (Cervoni and Szyf, 2001; Mund et al., 2006; Milutinovic et al., 2007; Dong et al., 2007). Although the expression of DNA demethylases is still controversial, it seems clear that histone deacetylase inhibitors, such as valproic acid and MS-275, act to inhibit deacetylases and alter cellular DNA promoter methylation patterns. The concept of demethylation in the regulation of neuronal gene expression has been suggested in the context of cognitive development (Hong et al., 2000) and memory formation (Levenson and Sweatt, 2005).

We propose the scheme outlined in Fig. 1 to explain the epigenetic origins of Sz as it relates to concepts presented thus far. As shown, increased expression of Dnmt1 is thought to be associated with selective promoter hypermethylation and mRNA downregulation. Some of the downregulated mRNAs in GABAergic neurons include reelin, GAD1, SST, VGAT, Gat-1, NR2s, and the Dlx transcription factors (Guidotti et al., 2005; Beneyto and Meador-Woodruff, 2007; Benes et al., 2007). The observation that Dnmt1 is overexpressed in GABAergic neurons of Sz patients is consistent with the idea that a dysfunction of an epigenetic promoter hypermethylation mechanism may be at the heart of Sz (Veldic et al., 2004; 2005). In addition, using Dnmt1 antisense oligonucleotides, we have shown that Dnmt1 protein knockdown prevents the Met-mediated decrease in reelin and GAD1 mRNAs in cortical neurons maintained in vitro (Noh et al., 2005). While the role of Dnmt1-, 3a-, and 3b-mediated changes in gene-specific methylation is well known in the context of cancer biology (Szyf, 2005), very little is known regarding methylation as a regulatory mechanism in neurons. Currently, we do not understand what causes this (Dnmt1) increase in Sz, but it could be related to an as yet unknown upregulation of the Dnmt1 gene in response to hormonal surges that occur during or just after puberty (possibly estrogen or other hormones). This would account for the observations that 1) reelin downregulation from birth leads to a more severe pathological phenotype (Hong et al., 2000) and 2) the onset of Sz symptoms very rarely occurs before puberty. While this idea remains unproven, it provides an appropriate framework for testing hypotheses related to the temporal regulation of Dnmts1 in humans as it is linked to various hormonal influences that may act at the level of the corresponding promoters. This suggestion also implies the possibility that Dnmt1 inhibitors may be appropriate in the context of drug discovery for psychosis.

As neuron-specific and developmental expression patterns are accompanied by distinct alterations in chromatin structure and DNA methylation status (Razin, 1998; Sharma et al., 2005), it is important to focus on how the methylation of critical cytosines in these sequences affects the access of transcription factors to their recognition sites. Based on our data, we suggest that methylation represents a switch that can be used to regulate promoter expression under appropriate conditions (Kundakovic et al., 2007). An important concept that has been reinforced by many studies is that increased methylation increases the recruitment of methyl CpG binding proteins to the promoter, inducing a repressed or silenced chromatin state (Grayson et al., 2005; Dong et al., 2005). Whether the so-called "methylation switch" is reversible is still open to exploration. Recent data suggest that developmental changes induced in the absence of MeCP2 from birth are reversible and the implications are that these alterations may be consistent with methylation acting dynamically to modulate promoter expression (Guy et al., 2007). It will now be important to address whether other promoters known to be downregulated in Sz share a similar sensitivity to changes in methylation.

New prospects for treatment should target DNA methyltransferases and histone deacetylases?
We have hypothesized that promoter methylation is likely a reversible event. For example, the hypermethylation of the hippocampal glucocorticoid receptor gene in the offspring of maternal grooming-deficient rats can be erased by the administration of histone deacetylase inhibitors (Szyf et al., 2007). Recent evidence obtained in Met-treated mice indicates that reelin and GAD1 promoter hypermethylation can be effectively reversed by valproic acid and other histone deacetylase inhibitors. This allows us to infer that in addition to Dnmts and SAM, a DNA demethylase may play a key role in regulating the steady-state levels of promoter methylation in neurons of the brain (Dong et al., 2007). The molecular nature, kinetics, and expression of a brain demethylase activity remains an important topic of study in the area of Sz pathophysiological treatment. In fact, an induction of this activity elicited by clozapine but not by haloperidol may explain the greater antipsychotic efficacy of clozapine compared to earlier antipsychotics (Erbo Dong et al., unpublished data).

The ultimate goal of epigenetics research in the context of psychiatry at this point in time is to better understand the regulation of multiple genes expressed in GABAergic neurons so that we can identify therapeutic targets for the treatment of Sz (Costa et al., 2003a ; 2003b; 2006; 2007; Guidotti et al., 2005; Grayson et al., 2006). Once the scientific community has a solid understanding of the regulatory cascades shared by multiple promoters/transcription units, it may be possible to devise more appropriate and more efficacious ways to intervene to reactivate gene expression (Mund et al., 2006; Kundakovic et al., 2007; Levenson, 2007). The impact of this hypothesis extends beyond Sz and includes other disorders including bipolar disorder, depression, addiction, and a variety of autistic-like disorders that occur during brain development (see Tsankova et al., 2007, for recent review).

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Comment by Chris Turck

I am very intrigued by the interesting link between methionine and psychosis the authors discuss in their hypothesis article. Clinical studies from the 1960s where treatment with high doses of methionine elicited acute psychotic episodes in patients who had been previously symptomatic for schizophrenia could now be explained by epigenetic effects of the amino acid. Based on mouse studies, Grayson and colleagues showed that methionine mediates changes in gene expression and promoter methylation through an increase in brain S-adenosylmethionine levels, the major methyl donor in cells and tissues.

Other literature suggests that S-adenosylmethionine has antidepressant activities (Bressa, 1994; Kagan et al., 1990). In fact, this compound is sold over the counter as a mood stabilizer (SAMe). How can these apparently opposite activities, exacerbation of psychotic symptoms in schizophrenia patients, and antidepressant effects in affective disorder patients be reconciled?

References:
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Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 1990 May 1;147(5):591-5. Abstract

Reply by Alessandro Guidotti to Chris Turck

The methionine studies in chronic schizophrenia patients support the hypothesis that psychotic symptoms may be due to an overeactive methylation system in selected populations of telencephalic GABAergic neurons. In contrast, depression has been associated with low brain folate levels, a key intermediate in methionine metabolism, which may result in a downregulation of the methylation system (Smythies, 1984). In support of this hypothesis there are reports that parenteral administration of SAM, a methyl group donor, results in an effective antidepressant treatment, although there are reports showing that SAM can switch depressed patients from depression to mania (Carney et al., 1983). It must be stressed that there have been many difficulties reported in using SAM parenterally as a therapeutic agent in depression arising from inconsistencies of the parenteral absorption and from the chemical instability of the compound at physiological plasma pH.

References:
Smythies JR. Trends Neurosci. 1984;7: 45-47.

Carney MW, Martin R, Bottiglieri T, Reynolds EH, Nissenbaum H, Toone BK, Sheffield BN. Switch mechanism in affective illness and S-adenosylmethionine. Lancet. 1983 Apr 9;1(8328):820-1. Abstract