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.
Recently our laboratory has discovered a signaling pathway that combines elements of all four of these theories. Our research found that dopamine can stimulate the methylation of membrane phospholipids via the activation of the D4 dopamine receptor. Furthermore, we found that the D4 receptor is complexed to NMDA receptors, suggesting that the methylation of phospholipids could regulate NMDA receptor activity. Only in man and primates does the D4 receptor possesses a repeat structural feature, facilitating its complexation with synaptic NMDA receptors. This finding suggests that schizophrenia may result from an impairment in the ability of D4 dopamine receptors to modulate NMDA receptors at nerve synapses via phospholipid methylation. This modulation may be important for the normal attention and cognitive abilities of man.
Certainly more research is necessary to follow-up on the clues provided by these results. There is reason to hope, though, that new findings will not only make the cause of schizophrenia clearer, but will also lead to novel, more effective treatments.