The Single-Carbon Hypothesis: Researchers have often linked disturbances of the single-carbon folate pathway to schizophrenia. This metabolic pathway provides carbon groups for a variety of biochemical reactions in the brain, including the synthesis of purine and pyrimidine nucleotides and the methyl-donating amino acid methionine. A number of studies have shown that methionine metabolism is impaired in most schizophrenic persons, and other work has demonstrated enzyme deficits in the folate pathway in some schizophrenic persons. These observations are clear, but their relationship to neuronal transmission has remained elusive.
The Membrane Hypothesis: Nerves are largely composed of phospholipid membranes, and phospholipid metabolism is critical to normal brain function. Neurotransmitter receptors, such as dopamine and NMDA receptors, function within the membranes of nerve cells–and so disturbances of the membrane structure could readily affect how neurons transmit messages across nerve synapses. Studies have demonstrated that a deficit in the level of highly unsaturated fatty acids is associated with schizophrenia, as is decreased activity of the enzyme phospholipase A2, which breaks down membrane phospholipids. These observations suggest that an impairment in the transmission of signals across cell membranes may be responsible for schizophrenia.