The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.

Postmortem prefrontal cortices (PFC) (Brodmann's areas 10 and 46), temporal cortices (Brodmann's area 22), hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects were compared for reelin (RELN) mRNA and reelin (RELN) protein content. In all of the brain areas studied, RELN and its mRNA were significantly reduced (Ϸ50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. To exclude possible artifacts caused by postmortem mRNA degradation, we measured the mRNAs in the same PFC extracts from ␥-aminobutyric acid (GABA) A receptors ␣ 1 and ␣ 5 and nicotinic acetylcholine receptor ␣ 7 subunits. Whereas the expression of the ␣ 7 nicotinic acetylcholine receptor subunit was normal, that of the ␣ 1 and ␣ 5 receptor subunits of GABA A was increased when schizophrenia was present. RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum. A protein putatively functioning as an intracellular target for the signaltransduction cascade triggered by RELN protein released into the extracellular matrix is termed mouse disabled-1 (DAB1) and is expressed at comparable levels in the neuroplasm of the PFC and hippocampal pyramidal neurons, cerebellar Purkinje neurons of schizophrenia patients, and nonpsychiatric subjects; these three types of neurons do not express RELN protein. In the same samples of temporal cortex, we found a decrease in RELN protein of Ϸ50% but no changes in DAB1 protein expression. We also observed a large (up to 70%) decrease of GAD67 but only a small decrease of GAD65 protein content. These findings are interpreted within a neurodevelopmental͞vulnerability ''twohit'' model for the etiology of schizophrenia.

We recently reported that f luoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3␣-hydroxy-5␣-pregnane-20-one (3␣5␣-ALLO) without altering the brain content of other neurosteroids. ALLO (3␣5␣ and 3␣5␤ isomers) binds with high affinity to various ␥-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal f luid (CSF) before and 8-10 weeks after treatment with f luoxetine or f luvoxamine in 15 patients with unipolar major depression. The concentration of ALLO (Ϸ40 fmol͞ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, f luoxetine or f luvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r ‫؍‬ 0.58; P < 0.023; n ‫؍‬ 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after f luoxetine or f luvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of f luoxetine or f luvoxamine via its positive allosteric modulation of GABA type A receptors.Fluoxetine, fluvoxamine, and other selective 5HT reuptake inhibitors (SSRIs) have a spectrum of therapeutic actions that is broader than that of the monoamine oxidase inhibitors or the tricyclic imipramine-like antidepressants (1-5). Because several lines of evidence indicate that the action of various antidepressant classes is related to an enhancement of serotonin (5HT)-mediated neurotransmission and SSRIs are more selective in inhibiting 5HT reuptake than tricyclic antidepressants (6), it is possible that the therapeutic properties that are exclusively elicited by SSRIs may not depend only on 5HT neurotransmission for their action.We have recently reported that fluoxetine and paroxetine, two SSRIs, but not imipramine, when administered to rats, increase the steady-state brain content of the neurosteroid 3␣-hydroxy-5␣-pregnane-20-one (3␣5␣-ALLO), without altering the brain content of other neurosteroids (7) (for chemical structure and biosynthetic pathways of neurosteroids, see Fig.

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 ...

No abstract