Schizophrenia: Hereditarily-Conditioned Synapcide?

3. May 2016

The aetiology of schizophrenia has until now been unclear. Researchers have now discovered that certain gene variants are associated with an increased risk of schizophrenia and may lead to excessive pruning of synapses during adolescence.

Worldwide about 1% of the population is at least once in life affected by schizophrenia. Characteristic features include fundamental disturbance of thought, perception and experiences, which can range from the perception of reality being impaired to it being fully lost. The heritability of the disease is often stated to be 81%, which indicates a strong genetic influence.

Long-standing mystery solved

A previous study already identified 108 schizophrenia-associated loci, among which the MHC region on chromosome 6 showed the highest association with disease risk. This genetically very complex region includes hundreds of genes, many of which are known for their influence on immune function – exactly which gene increases the risk of schizophrenia remained until now just as unclear as the causative biological process involved. “Since being first described more than a century ago, the underlying biology of schizophrenia has been a ‘black box’, partly because it has practically been impossible to reproduce the disease within cell or mouse models”, explains Steven McCarroll, one of the lead authors of the newly published study [Paywall]. “The human genome provides a powerful new pathway to approach this disease. Understanding the genetic influence on the risk provides a way to pry the ‘black box’ open, to look inside and to begin to glimpse the real biological mechanisms there”.

For this reason the groups led by McCarroll and his colleagues Beth Stevens and Michael Carroll from Harvard Medical School, the Broad Institute and the Boston Children’s Hospital, analysed the genomes of 28,799 patients with schizophrenia and 35 986 control subjects. In addition, the researchers studied 700 brains of deceased people and made use of gene modification-based mouse model options. During the search for the gene responsible for schizophrenia, the researchers had to develop completely new case analysis methods. Their focus was quickly shifted onto the complement factor C4 genes in the MHC locus which are distinguished by a surprisingly high structural variability. The genomes of different people have a highly differing number of gene copies and also four different variants (C4A and C4B, respectively as short and long variants). The researchers then established that there was a striking pattern: in schizophrenia patients in particular those C4 variants were found which promote the expression of C4A in the brain tissue.

New role for an old acquaintance

The complementary factor C4 was previously known for its role in the innate immune system. There it marks the surface of certain micro-organisms and thus mediates opsonisation. Pathogens can be detected more easily as being foreign in this way and subsequently eliminated by phagocytic cells. The researchers were then able to demonstrate in the mouse model a similar, previously unknown function in the brain: here C4 seems to ensure that another complement factor (C3) gets deposited on the synapses. This serves as a signal for ‘pruning’ of the synapses by microglia cells. In addition, the researchers found the more C4 copies were contained in the genome of mice, the greater was the degree of trimming of synapses.

Pruning is a normal process [Paywall] that takes place during the maturation of the brain and ensures, following the “use it or lose it” principle, that only those synapses are retained which are often used. The study data now indicate that excessive marking of synapses occurs in individuals possessing schizophrenia-risk variants of C4, causing more synapses to be eliminated than is normal. This could be the cause of schizophrenia-typical cognitive symptoms and also explain why the schizophrenia patient’s brain tends to have less grey matter and exhibit a thinner cortex cerebri. And it could also be the reason why the disease typically occurs during adolescence and young adulthood: it’s especially during this stage of development that marked pruning processes occur in the brain.

(Still) just glances into the future: treating the cause rather than symptoms

The results of the study seem to tempt many to harbour great optimism. “This study marks a turning point in the fight against mental illness”, says, for example, Bruce Cuthbert, executive director of the US National Institute of Mental Health, which co-financed the study. “Since the molecular causes of psychiatric disorders are little understood, there have been only isolated efforts by pharmaceutical companies to develop new therapeutics. With this study, the cards have been reshuffled. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments and prevention”.

Should the new results actually allow a curative treatment of schizophrenia, a great advance would then be at hand, because until now only the symptoms of the condition have been able to be treated. A screening of patients at risk does seem feasible, however study author McCarroll advises caution: “A genetic test is not recommended by us. The value of [this discovery] is that the gene has allowed this new insight into the biology which lies at the base of schizophrenia. We hope that this will lead in time to completely new medical approaches that treat the causal disease mechanism”.

Disease risk: genetics + environment

Peter Falkai, director of the Department of Psychiatry, University of Munich, Germany, sees things similarly. For him, a genetic test at this point in time does not yet make sense: “All the data with which we are working here shows that the genetic information that we have at the moment does not really lead to a clean forecast”. For him the predictive value of the genetic schizophrenia marker still needs to prove itself. “We need long-term studies involving several thousand participants before we can say whether the genetic knowledge gleaned allows statements to be made about the transition to a psychosis or about the course of the disease”. He also warns about limiting ourselves to the analysis of individual genes – social factors could in fact be just as important in the pathogenesis of schizophrenia. “One has to look at both: the genetic setup, with which someone goes into an environment, and the environment, which acts in concert with it”, explains Falkai.

Until new, treatment-based approaches based on the complement system are ready for everyday use in the clinic and hospital, for the doctors and patients concerned the only remaining option is the use of previously recommended standard therapy consisting of psychotherapeutic and socio-theraflowcomm, flickrpeutic measures and pharmacological interventions using antipsychotics. Atypical antipsychotics such as risperidone, quetiapine and olanzapine should be given preference, when possible, to conventional antipsychotics such as haloperidol, flupentixol or perphenazine. An adjuvant can be employed in the form of benzodiazepine, anticonvulsant, lithium and antidepressant.

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