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January 28, 2016

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Schizophrenia tied to excess trimming of connections in brain

Jan. 28, 2016
Courtesy of Nature
and World Science staff

Schiz­o­phre­nia may arise as a re­sult of the brain ex­ces­sively trim­ming the num­ber of con­nec­tions among nerve cells dur­ing youth—a nor­mal pro­cess, gone awry, a new study sug­gests.

Sci­en­tists said the find­ings could shed im­por­tant light on the poorly un­der­stood bi­o­log­i­cal causes of the de­vastating men­tal ill­ness.

Imaging studies showed C4 (in green) located at the synapses of primary human neurons. (Credit: Image courtesy of Heather de Rivera (McCarroll lab))


Re­search­ers in the study found that genes most of­ten mu­tat­ed in schiz­o­phre­nia pa­tients could al­so be tied to the nat­u­ral pro­cess of trim­ming brain cell con­nec­tions—known as syn­ap­tic prun­ing—at least in mice.

Syn­ap­tic prun­ing oc­curs in hu­mans as well and in­volves the brain re­duc­ing its num­ber of synapses, or con­nec­tions that trans­fer mes­sages among nerve cells. The pro­cess runs from around the time of birth to pu­ber­ty and is thought to en­a­ble the brain to fo­cus in­forma­t­ional re­sources where they’re most use­ful.

The new stu­dy, pub­lished in the re­search jour­nal Na­ture this week, re­ported a de­tailed map­ping of the ge­net­ic varia­t­ions most strongly as­so­ci­at­ed with schiz­o­phre­nia. The re­sults sug­gested that com­plex struc­tur­al varia­t­ion in a hard-to-map re­gion of the ge­nome called the ma­jor his­to­com­pat­ibil­ity com­plex, or MHC, fa­cil­i­tates the over­ac­tiva­t­ion of a gene called com­ple­ment com­po­nent 4. 

Al­though that gene is known for an im­mune sys­tem role, the au­thors showed that hu­man C4 pro­tein is al­so found at synapses. They al­so used a mouse mod­el to show that C4 con­trols the elimina­t­ion of synapses dur­ing syn­ap­tic prun­ing.

The au­thors, Ste­ven Mc­Car­roll Har­vard Med­i­cal School and col­leagues, an­a­lyzed the brains of or­gan donors with or with­out schiz­o­phre­nia to un­der­stand how DNA varia­t­ion af­fect­ed ac­tiva­t­ion of two dif­fer­ent forms of the gene. They then found, by an­a­lyz­ing DNA from 64,785 peo­ple from 22 coun­tries, that risk of the disease is most strongly as­so­ci­at­ed with ge­net­ic varia­t­ion that in­creases ac­tiva­t­ion of C4A in the brain.

Schiz­o­phre­nia, a se­vere, her­it­a­ble brain dis­or­der, in­volves im­pair­ments in cog­ni­tion, per­cep­tion and mo­tiva­t­ion that usu­ally beg­in in ad­o­les­cence or early adult­hood. Al­though loss of brain tissues and re­duced num­bers of synapses be­tween brain cells have been seen in the brains of pa­tients, the un­der­ly­ing cause of schiz­o­phre­nia re­mains un­known.


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Schizophrenia may arise as a result of the brain excessively trimming the number of connections among nerve cells during youth—a normal process, gone awry, a new study suggests. Scientists said the findings could shed important light on the biological causes of a mental illness whose origins are poorly understood. Researchers in the study found that genes most often mutated in schizophrenia patients could also be tied to the natural process of trimming brain cell connections—known as synaptic pruning—at least in mice. Synaptic pruning occurs in humans as well and involves the brain reducing its number of synapses, or connections that transfer messages among nerve cells. The process runs from around the time of birth to puberty and is thought to enable the brain to focus informational resources where they’re most useful. The new study, published in the research journal Nature this week, reported a detailed mapping of the genetic variations most strongly associated with schizophrenia. The results suggested that complex structural variation in a hard-to-map region of the genome called the major histocompatibility complex, or MHC, facilitates the overactivation of a gene called complement component 4. Although that gene is known for an immune system role, the authors showed that human C4 protein is also found at synapses. They also used a mouse model to show that C4 controls the elimination of synapses during synaptic pruning. The authors, Steven McCarroll Harvard Medical School and colleagues, analyzed the brains of organ donors with or without schizophrenia to understand how DNA variation affected activation of two different forms of the gene. They then found, by analyzing DNA from 64,785 people from 22 countries, that risk is most strongly associated with genetic variation that increases activation of C4A in the brain. Schizophrenia, a severe, heritable brain disorder, involves impairments in cognition, perception and motivation that usually begin in adolescence or early adulthood. Although loss of brain grey matter and reduced numbers of synapses between brain cells have been seen in the brains of patients, the underlying cause of schizophrenia remains unknown.