The biological process resulting in the development of schizophrenia may have finally been discovered, after researchers conducted a detailed genetic analysis of more than 60,000 people in an attempt to decipher which genomic characteristics are most strongly associated with the disorder.
Schizophrenia is a heritable condition that tends to become apparent in late adolescence and young adulthood, and is characterized by cognitive impairment, emotional instability, and hallucinations. During these years, most people undergo a process called synaptic pruning, whereby the connections between some neurons – or synapses – are eliminated.
While some degree of synaptic pruning is normal at this stage of life, in extreme cases it can cause an abnormal reduction in the volume of grey matter tissue and synaptic structures in regions of the brain that are strongly associated with high-level cognition and emotional control, such as the prefrontal cortex. This is precisely what is observed in schizophrenic individuals, although while scientists have been aware of this effect for some time, the mechanisms that cause such extensive synaptic pruning had until now remained poorly understood.
To try and solve this riddle, researchers analyzed the genetic data of 28,799 schizophrenics and 35,896 non-schizophrenics, using information collected as part of the Psychiatric Genetics Consortium. In particular, they focused on those genes contained within a region of the human genome, located on chromosome six, that codes for the major histocompatibility complex (MHC). Though this protein is mostly known for the role it plays in immunity, the genes in the MHC region have previously shown to contain a number of genetic markers that are associated with schizophrenia.
Schizophrenics are known to have reduced numbers of synapses in their brains. nobeastsofierce/Shutterstock
Reporting their findings in the journal Nature, the study authors found a strong correlation between the development of schizophrenia and the presence of a particular variation of the gene C4. This gene can exist in multiple forms, which code for the expression of two different proteins, known as C4A and C4B. Those variations that result in an increased expression of C4A were found to be strongly associated with schizophrenia.
Both C4A and C4B promote the activation of another protein called C3, which attaches to certain targets within the brain and spinal cord in order to mark them out for destruction by immune cells called microglia. When C3 attaches to subsets of synapses, these are then eliminated by these cells, resulting in synaptic pruning.
Precisely why and how C4A causes excess synaptic pruning to occur while C4B does not is unknown, although the fact that the two proteins produce different effects is hardly unexpected, given the large biochemical differences between the two. For instance, C4A readily bonds with other proteins, while C4B favors binding with carbohydrates. It is therefore likely that the two forms of the protein attach to different binding sites at synapses, although more information is needed to elaborate on this.
Commenting on these findings, Bruce Cuthbert, acting director of the National Institute of Mental Health, said the study “changes the game” in the fight against mental illness, as it may lead to the development of new therapies that treat the causes rather than just the symptoms of schizophrenia.
