More clues to understanding schizophrenia
Friday, January 29, 2016
The exact causes of schizophrenia, which affects about one in every 100 adults worldwide and more than two million Americans, have eluded physicians and scientists for centuries. Although available drugs to treat this disorder may blunt some of the symptoms, such as delusions and hallucinations, they do not treat the underlying causes.
Two theories have for decades dominated research on the causes of schizophrenia: genetics and neurotransmitters.
Over the past two years, a third theory — the infectious/inflammatory theory — has become the first major new addition to schizophrenia study in the last half-century and, with less evidence, to the study of bipolar disorder and depression. This theory states that infections play an important role in causing schizophrenia, probably in conjunction with predisposing genes or the effects of infectious agents on neurotransmitters.
However, recently, scientists believe they have taken a significant additional step toward understanding the cause of schizophrenia in a study that provides the first rigorously tested insight into the biology behind any common psychiatric disorder.
The researchers at Columbia University Medical Center in New York City pieced together the steps by which genes can increase a person's risk of developing schizophrenia. That risk, they found, is tied to a natural process called synaptic pruning, in which the brain sheds weak or redundant connections between neurons as it matures. During adolescence and early adulthood, this activity takes place primarily in the brain’s prefrontal cortex where thinking and planning skills are centered.
The researchers at Columbia knew that schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. In this study, the researchers show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes.
They found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons and cell bodies. In mice, C4 mediated synapse elimination during postnatal development.
These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia. Some researchers had suspected that the pruning must somehow go awry in people with schizophrenia because previous studies showed that their prefrontal areas tended to have a diminished number of neural connections compared with those of unaffected people.
This study not only strongly supports that this is the case, but also describes how the pruning probably goes wrong, why the pruning goes wrong, and identifies the genes responsible. In essence, those with schizophrenia have a gene variant that apparently facilitates aggressive "tagging" of connections for pruning, in effect accelerating the process.
This landmark study suggests that people who carry genes that accelerate or intensify that pruning are at higher risk of developing schizophrenia than those who do not.The finding, published in Nature, will not necessarily lead to new treatments soon nor to widely available testing for individual risk. But the results provide researchers with their first biological handle on an ancient disorder whose cause has confounded modern science for generations. The finding also helps explain some other mysteries, including why the disorder often begins in adolescence or young adulthood.
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