Schizophrenia is a psychiatric disorder in which previously normal cognitive abilities and behaviors becomes disturbed. The most common age of onset is just after reaching adulthood, typically the late-teens to the mid-thirties. It is manifested either by so-called positive symptoms (delusions, hallucinations, unusual or disorganized behavior) or by negative symptoms, including a marked lack of activity, loss of interest and unresponsiveness.
Although the precise cause of schizophrenia remains unknown, an enormous amount of research has come up with a number of possibilities. Many early theories focused on behavioral or stress-induced events, but more recently, consensus holds that underlying biochemical abnormalities are more likely the cause. Lending great support to this idea is the fact that genetic predisposition may account for 50 percent of the risk of developing schizophrenia. Not surprisingly, these biochemical hypotheses center on dysfunction of the neurotransmitter systems in the brain, which provide for normal cognition and attention. The main theories include the Dopamine Hypothesis, the NMDA Receptor Hypothesis, the Single-carbon Hypothesis and the Membrane Hypothesis. And new research from our laboratory suggests that elements from each of these theories may play a role in schizophrenia.
The Dopamine Hypothesis: The notion that dopamine may be involved in schizophrenia derives from the therapeutic usefulness of drugs that block certain dopamine receptors in treating the disorder. Indeed, because dopamine blockers are so often effective, it has been proposed that an over activity of dopamine neurotransmission in cortical and limbic areas of the brain may cause schizophrenia. Drugs with selectivity for the D4 dopamine receptor (such as clozapine or olanzapine) can be particularly effective, and so this receptor subtype may play a critical role; in fact, elevated levels of D4 receptor binding have been found post-autopsy in the brains of persons who had schizophrenia. Dopamine is further implicated by the fact that a schizophrenia-like psychosis can be induced by abusing amphetamines, which act on dopamine pathways.
The NMDA Receptor Hypothesis: NMDA receptors respond to the excitatory neurotransmitter glutamate, and are known to be important for normal memory and cognition. Because drugs affecting NMDA receptors (such as ketamine or phencyclidine (PCP)) can cause schizophrenia-like hallucinations and because neuroleptic drugs, including clozapine, can inhibit their occurrence, it has been suggested that NMDA receptor dysfunction may cause schizophrenia. Recent studies have shown therapeutic benefit from drugs acting on NMDA receptors, such as glycine and D-cycloserine.
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.
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.