Reelin mRNA and protein levels are reduced by Ϸ50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair ؊527 to base pair ؉322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions ؊134 and ؊139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.DNA methyltransferase ͉ epigenetics ͉ gene regulation ͉ methylation ͉ psychiatric disorder S chizophrenia is a devastating disorder with a populationwide morbidity approaching 1%. The genetics of the disease are perhaps one of the most studied facets of schizophrenia, but the results of multiple linkage analyses have not provided a clarification of underlying etiological factors that define the symptomatology of the disease (1, 2). However, insight has come from recent reports that examined biological markers that appear to be aberrantly regulated in postmortem brains of patients diagnosed with schizophrenia (3-5). It was noted that among Ͼ100 different markers examined, reelin and glutamic acid decarboxylase (GAD) 67 are the most abnormal in the context of schizophrenia and bipolar illness (6). These two mRNAs and their cognate proteins are selectively coexpressed in GABAergic neurons of the mammalian cortex. The observation that reelin and GAD 67 are down-regulated has been one of the more consistently replicated findings observed in postmortem cortex from schizophrenia patients (SZP). We previously reported reelin mRNA and protein levels are quantitatively reduced by Ϸ50% in various cortical structures of postmortem brain from SZP and bipolar patients (3, 4). The results obtained with respect to reelin were independently confirmed immunohistochemically in the hippocampus (7) and ...
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...
Rats suppress intake of an acceptable substance (e.g., 0.15% saccharin) when it is followed by a preferred substance (e.g., 32% sucrose) in once per day pairings. The role of a learned devaluation of the initial solution in suppressed intake (anticipatory negative contrast) was investigated. The findings included the following: (a) Flavors or odors as within-subject cues precluded the occurrence of anticipatory contrast, conditioning flavor and odor preferences instead, which appeared to antagonize suppressed intake. (b) Anticipatory contrast was obtained when within-subject context cues, temporal alternation cues, or drinking-spout cues were used. (c) Preference tests conducted with the spout cues showed that devaluation of the initial substance was not necessary for the occurrence of negative anticipatory contrast.
We investigated the effects of agents that induce reelin mRNA expression in vitro on the methylation status of the human reelin promoter in neural progenitor cells (NT2). NT2 cells were treated with the histone deacetylase inhibitors, trichostatin A (TSA) and valproic acid (VPA), and the methylation inhibitor aza-2¢-deoxycytidine (AZA) for various times. All three drugs reduced the methylation profile of the reelin promoter relative to untreated cells. The acetylation status of histones H3 and H4 increased following treatment with VPA and TSA at times as short as 15 min following treatment; a result consistent with the reported mode of action of these drugs. Chromatin immunoprecipitation experiments showed that these changes were accompanied by changes occurring at the level of the reelin promoter as well. Interestingly, AZA decreased reelin promoter methylation without concomittantly increasing histone acetylation. In fact, after prolonged treatments with AZA, the acetylation status of histones H3 and H4 decreased relative to untreated cells. We also observed a trend towards reduced methylated H3 after 18 h treatment with TSA and VPA. Our data indicate that while TSA and VPA act to increase histone acetylation and reduce promoter methylation, AZA acts only to decrease the amount of reelin promoter methylation.
The hippocampal formation (HF) is one of the brain structures most consistently altered in schizophrenia, yet the contribution of HF pathology to severe mental illness is poorly understood. We present evidence that our current ignorance is attributable to the fact that the anterior HF is heavily involved in schizophrenia but has been inadequately examined by schizophrenia investigators. We propose that the anterior HF in humans, and its counterpart in rodents (ventral HF), constrain diverse responses to psychological stimuli and that disruption of this function contributes to schizophrenia. While current data suggest that hallmark symptoms of schizophrenia most likely result from the role of the anterior HF in the integrated neurocircuit that includes the prefrontal cortex, ventral striatum, and ventral tegmental area, better characterized and phylogenetically preserved neurocircuits may be similarly affected by anterior HF pathology and account for associated findings of the disorder. We propose that focusing on the impact of ventral HF pathology on these simpler circuits and functions in rodents may provide insight into the pathophysiology of severe mental illness in humans. We review several associated findings in schizophrenia to assess the likelihood that each could be a product of this putative anterior HF dysfunction and could therefore be productively studied in rodents by probing ventral HF function.
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