Genetic Disorder Points to Cellular Communication Problems in Schizophrenia

Genetic Disorder Points to Cellular Communication Problems in Schizophrenia

Posted: May 11, 2015

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The loss of a small piece of chromosome 22 leads to a developmental disorder known as 22q11.2 deletion or DiGeorge syndrome that is characterized by abnormalities in the heart, brain, muscles and other bodily systems. People with this syndrome frequently experience cognitive and emotional problems. Around one-third develop schizophrenia later in life – many more than the 1% of the general population who develop the illness – so researchers are probing the roughly 45 genes normally in the deleted region, hopeful that they may provide clues to brain abnormalities in schizophrenia.

New findings published online April 23rd in the journal Neuron use two different mouse models of 22q11.2 deletion syndrome to find abnormalities in communication between neurons that provides a potential explanation for some of the findings in schizophrenia. The researchers find that removing a region in the mouse genome akin to the piece of chromosome that is absent in humans with 22q11.2 deletion syndrome results in shorter and less complex axon branches, the snake-like projections that neurons use to communicate. This appears to result in brain regions being less well connected that in control mice. The researchers also found similar, though less robust, differences in the axons and brain connectivity of mice who had just one of the 45 genes deleted, suggesting that this particular gene, ZDHHC8, may play a large role in the communication problems.

The new study, led by two-time Foundation Young Investigator Grantee Joseph Gogos, M.D., Ph.D., of Columbia University in New York City, also uncovers the molecular signaling pathway that contributes to these neuronal communication deficits, and finds that blocking the action of an enzyme called GSK3β can reverse the axon branching deficits. Future studies will examine whether lower levels of GSK3β can improve the schizophrenia-like connectivity and cognitive deficits also found in these mice.

Additional Grantees who took park in the study were two-time Foundation Grantee Jun Mukai, M.D., Ph.D., of Columbia University, Maria Karayiorgou, M.D. (1998 Young Investigator Grantee and 2010 Distinguished Investigator Grantee) and Joshua A. Gordon, M.D., Ph.D. (two-time Young Investigator Grantee and Foundation Scientific Council Member) both of the New York State Psychiatry Institute.

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