Comment by Dennis R. Grayson, Erminio Costa, and Alessandro Guidotti
Schizophrenia is a devastating disorder with a population-wide morbidity approaching 1 percent. The genetics of this disease are perhaps the most studied facet of the disorder, but the results of multiple linkage analyses across the entire genome have provided only limited insight into the underlying etiological factors that hallmark the disease. While linkage studies are informative, problems associated with the interpretation of complex genetics 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 the disease may lie in DNA sequence variations coupled with epigenetic dysfunction as a key etiopathogenic factor.

Several studies point to a defect in GABAergic transmission as a key factor underlying the schizophrenia phenotype. Over 10 years ago, a decrease in GAD67 (GAD1) expression and an increase in selected GABA-A receptor subunits in the frontal cortex of patients with schizophrenia was reported (Akbarian et al., 1995). We replicated and extended this finding to include reelin and GAD1 in frontal cortex (Impagnatiello et al., 1998; Guidotti et al., 2000), while others have since reported comparable findings in the hippocampus (Heckers et al., 2002). Numerous laboratories have proposed that the reduced expression of reelin, GAD1, and other mRNAs results in a decrease in interneuron inhibitory tone that has been described in schizophrenia patients (reviewed in Benes and Berretta, 2001; Guidotti et al., 2005; Lewis et al., 2005). The decreased inhibitory tone may cause a downregulation in post-synaptic dendritic spine protein synthesis and a disruption of the synchronized high-frequency pyramidal neuron firing rates that characterize changes in cortical function.

The most common mechanism proposed to account for the epigenetic changes observed in GABAergic neurons of schizophrenia patients is CpG methylation (Costa et al., 2002; 2007). Several labs have examined the methylation patterns of reelin in postmortem human material (Abdolmaleky et al., 2005; Grayson et al., 2005). More recently, global methylation patterns have been shown to increase in the cortex of humans across the lifespan (Siegmund et al., 2007). In their current paper, Huang et al., 2007 discuss another potentially important means of modifying promoter function. That is, alterations in chromatin remodeling mediated by changes in histone methyltransferases in GABAergic neurons are likely to affect the accessibility of selected promoters to the transcriptional machinery. What makes the current study so interesting is that the investigators have found changes in multiple promoters expressed in these neurons including those of GAD1, neuropeptide Y, and somatostatin. Interestingly, the reduced levels of GAD1 mRNA correlate with increased GAD1 promoter H3K4 trimethylation. The histone methyltransferase responsible is mixed-lineage leukemia 1 (MLL1). Mice heterozygous for the Mll1 locus show reduced GAD1 H3K4 trimethylation at GABAergic gene promoters. In addition, GAD1 H3K4 trimethylation and Mll1 occupancy are increased following treatment with the atypical antipsychotic clozapine. It seems clear from these and other studies that the epigenetic origins of schizophrenia are becoming increasingly evident and that they operate on multiple levels. It remains to be seen how DNA methylation and histone methylation cooperate in this cascade and why the defect is localized to GABAergic neurons. Do these mechanisms act in concert, or do they act independently? It seems reasonable that DNA methylation and histone methylation may converge, effecting a similar end result.

References:

Abdolmaleky HM, Cheng KH, Russo A, Smith CL, Faraone SV, Wilcox M, Shafa R, Glatt SJ, Nguyen G, Ponte JF, Thiagalingam S, Tsuang MT. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):60-6. Abstract

Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995 Apr 1;52(4):258-66. Abstract

Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology. 2001 Jul 1;25(1):1-27. Abstract

Costa E, Chen Y, Davis J, Dong E, Noh JS, Tremolizzo L, Veldic M, Grayson DR, Guidotti A. REELIN and schizophrenia: a disease at the interface of the genome and the epigenome. Mol Interv. 2002 Feb 1;2(1):47-57. Abstract

Costa E, Dong E, Grayson DR, Guidotti A, Ruzicka W, Veldic M. Reviewing the role of DNA (cytosine-5) methyltransferase overexpression in the cortical GABAergic dysfunction associated with psychosis vulnerability. Epigenetics. 2007 Jan-Mar ;2(1):29-36. Abstract

Crow TJ. How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry. 2007 Jan 1;164(1):13-21. Abstract

Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9341-6. Abstract

Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000 Nov 1;57(11):1061-9. Abstract

Guidotti A, Auta J, Davis JM, Dong E, Grayson DR, Veldic M, Zhang X, Costa E. GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology (Berl). 2005 Jul 1;180(2):191-205. Abstract

Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2002 Jun 1;59(6):521-9. Abstract

Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15718-23. Abstract

Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005 Apr 1;6(4):312-24. Abstract

Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS ONE. 2007 Jan 1;2(9):e895. Abstract

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