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All in the Structure

In a new study in Nature Neuroscience, researchers at the Mount Sinai School of Medicine show that the reason some people with schizophrenia don't respond to antipsychotic drugs is because of the way the drugs affect DNA structure, reports Ed Yong at The Scientist. "[Javier] Gonzalez-Maeso and his colleagues found that antipsychotic drugs can suppress the expression of glutamate receptors in the brain, stunting their effectiveness as treatments for schizophrenia," Yong says. "But the researchers also found a way of boosting the effects of antipsychotics — by pairing them with drugs that block the gene suppression pathway."

Because antipsychotics change the structure of DNA in a way that inhibits mGlu2 expression, they end up suppressing both psychotic episodes and the effects of helpful glutamates.

"Mount Sinai's Mitsumasa Kurita used antibodies that recognize different types of histone modifications and found that clozapine, a second-generation antipsychotic drug, can alter the histones near a mouse's mGlu2 gene after just 3 weeks of treatment," Yong says. "The drug increases the levels of an enzyme called HDAC2, which alters the histones ahead of mGlu2 so they pack DNA more tightly. This silences the gene, and prevents glutamate receptors from being made. The result is worse psychotic symptoms."

Treating the mice with an inhibitor of HDAC2, the researchers reversed this effect, Yong adds.

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