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...