Two approaches for understanding schizophrenia gene DISC1 are reported at the Cold Spring Harbor in-house symposium

November 21, 2012

This week my lab attended the annual Cold Spring Harbor in-house symposium. We weren’t presenting this year, but heard about work from many labs here on campus. Some particularly interesting work focused on schizophrenia. Our interest in this topic stems from the fact that schizophrenics are known to have some abnormalities in how they use sensory information to guide behavior. 

A major challenge in understanding the genetic basis of mental illness is that for may diseases, multiple genes are clearly involved. In the case of schizophrenia and bipolar disorder, for example, the genetic basis is clear, but studies of large populations show that two patients who suffer from the same disorder may have very different underlying mutations. The discovery back in 1990 of a large Scottish family with a high instance of schizophrenia and shared disruption of a gene called DISC1 affords a rare opportunity to understand the connection between genes and disease. But much remains unknown! At the symposium this year, two labs took very different approaches to tackle this problem.

Dick McCombie talked about his lab’s use of a genetic approach to further understand the mechanism by which mutations in DISC1 lead to bipolar disorder or schizophrenia. They seek to identify which proteins interact with DISC1 in the hopes of better understanding how its disruption might lead to disease. This could be important in understanding why some family members are susceptible to the mental disorders while others are not: perhaps there are also mutations in the proteins with which DISC1 interacts in patients, leading to a greater mutational burden that results in disease.

Bo Li‘s lab presented a poster that took a different approach to understanding how DISC1 mutations lead to disease. The poster was presented by Watson School student Kristen Delevich who probed the effect on neural circuits of DISC1 mutations. She measured electrophysiological responses in the medial prefrontal cortex and compared their magnitude and frequency in wild type mice and those with DISC1 mutations. Further, she took advantage of technology developed by Josh Huang’s lab that allowed her to disrupt DISC1 only in specified classes of interneurons. The attached image demonstrates the technique: she used a DISC1 hairpin and restricted it to the desired class of neurons. This targeted approach could reveal whether DISC1 mutations preferentially disrupt inhibitory neurons, an appealing idea since a disruption in the balance of excitation and inhibition has been speculated to have devastating consequences for cognition.

Taken together, these two studies begin to close the gap between basic science and the clinic: Using genetic tools that reveal candidate sites of disruption alongside electrophysiological tools that probe mechanism is a powerful approach. Given the devastating nature of schizophrenia and bipolar disorders, and their frequency in the population, bridging this gap between the lab and the clinic is critical.

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One Response to “Two approaches for understanding schizophrenia gene DISC1 are reported at the Cold Spring Harbor in-house symposium”

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