Lymphocyte phospholipid methylation is altered in schizophrenia

An impairment in methylation reactions has previously been suggested to accompany and to cause schizophrenia. In an early hypothesis (“The transmethylation hypothesis”), a defect resulting in the formation of hallucinogens was proposed. Later, the “One-carbon hypothesis” suggested a defect in biochemical pathways involving methionine, S-adenosylmethionine and folic acid. We have recently discovered that the dopamine D4 receptor is a direct participant in the methylation of membrane phospholipids by virtue of its adenosylation at MET#313 and its subsequent donation of a methyl group. The D4 receptor, therefore, serves the role of methionine in supporting phospholipid methylation. In light of the suggested role of D4 receptors in people with schizophrenia we undertook studies to determine whether phospholipid methylation was altered. We studied males ages 27-70 with well documented schizophrenia by DSM-IV criteria, compared with normal controls. Lymphocytes were incubated for 1 hr. in [3H]methionine in the presence and absence of a combination of dopamine(10μM) and GTP (1mM) with and without haloperidol (10μM). Basal phospholipid methylation was approximately 3.5-fold lower in the patient samples, indicating a profound defect in this pathway. Dopamine/GTP stimulated methylation by an average of 30% in controls and by 165% in patients. Haloperidol inhibition reached 25% below basal in controls and 39% below basal in patients. These results confirm the presence of a defect in one-carbon metabolism in schizophrenia and show that this defect is remarkably prominent in the phospholipid methylation pathway involving the dopamine D4 receptor. Consequently, an altered membrane fluidity may play a significant role in producing the symptoms of schizophrenia.