Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia

Abstract

Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

“…A number of genes functioning in polyamine metabolism have also been implicated in schizophrenia through microarray analysis. 24 Polyamines themselves (primarily spermine but also spermidine) are known to modulate the activity of AMPA and NMDA subtype glutamate receptors. 25,26 Putrescine can be converted to GABA through an acetylated intermediate while glutamate is capable of modification to ornithine, the precursor of putrescine.…”

“…The selection of genes for validation was carried out on the basis of their involvement in stress response, neurodevelopment, connection to neurotransmitter pathways implicated in major depression and on the significance of findings from microarray analysis. 24.676.7 (SMD), F = 1.060, P = 0.357). There was no correlation between PMI and tissue pH within the PMI range of microarray study samples.…”

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

“…Studies of patients with schizophrenia have used microarray to screen cortical (DLPFC, superior temporal gyrus, and entorhinal cortex) and cerebellar samples from a matched set of subject to determine genes that are differentially expressed (3)(4)(5)(6)(7)(8)(9)(10)(11). Broadly, these reports to date have suggested alterations in functional pathways involving myelin, synaptic, metabolic, and proteasome-ubiquitin related processes in schizophrenia, though the specific differences, their magnitude and directionality, have been inconsistent.…”

“…These microarray comparisons used pools of RNA representing 20 patients and 20 controls. Another recent microarray study (6) reported that expression of the metabolic enzyme cytosolic malate dehydrogenase (MDH1) was decreased in the DLPFC of patients with schizophrenia, whereas another report showed the opposite (4). Neuroleptic treatment of monkeys increased MDH1 in the DLPFC (6).…”

“…Another recent microarray study (6) reported that expression of the metabolic enzyme cytosolic malate dehydrogenase (MDH1) was decreased in the DLPFC of patients with schizophrenia, whereas another report showed the opposite (4). Neuroleptic treatment of monkeys increased MDH1 in the DLPFC (6). Cocaine usage also dysregulated MDH1 in the DLPFC (12), raising the possibility that dopamine-related neurotransmission in the DLPFC can disturb MDH1 levels.…”