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New Study Finds Schizophrenia Risk Gene TCF4 Regulates Neuronal Activity

15 Mar 2016

March 16, 2016. A new study provides insights into how transcription factor 4 (TCF4), a gene that has been repeatedly associated with schizophrenia susceptibility, regulates the activity of neurons. While this study focused on another disorder, a type of autism called Pitt-Hopkins syndrome, its findings could provide a clue about molecular mechanisms that may underlie schizophrenia symptoms.

The study, published online on March 10 in the journal Neuron, was led by Brady Maher of the Lieber Institute for Brain Development in Baltimore, Maryland.

TCF4 has been linked to several neurodevelopment disorders, including Pitt-Hopkins syndrome (PTHS) and schizophrenia. TCF4 is a transcription factor—a gene that can either repress or activate the expression of various other genes. However, little is known about the genes regulated by TCF4 and how changes in expression of TCF4 could lead to its associated disorders.

Maher and colleagues explored these questions by using two rodent models of PTHS in which TCF4 protein had been reduced, or “knocked down.” They found that knocking down TCF4 severely decreased the firing of neurons in a part of the brain called the prefrontal cortex.

The team determined that the decrease in neuronal firing was likely caused by an increase in the expression of two ion channels (the parts of neurons that control how these cells communicate with one another)—KCNQ1 and SCN10a. Follow-up experiments showed that TCF4 binds directly to the KCNQ1 and SCN10a genes, suggesting that under normal conditions, TCF4 directly represses the expression of these genes.

The relevance of these findings for increasing our understanding of the biology of schizophrenia is unclear at this point—primarily because it is not known how, or even if, TCF4 expression is changed in people with schizophrenia. “The mechanism could be anything at this point. … We also don't know when during development it could matter,” said Maher, who told SRF his team is exploring this question using postmortem human brains at different developmental stages and in various clinical samples. (For more details, see the related news report.)—Summer E. Allen.