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New Molecules Could Be Used to Test Schizophrenia Hypothesis

24 Feb 2016

February 25, 2016. Several lines of research suggest that decreased activity of NMDA receptors, a type of protein that responds to the neurotransmitter glutamate, may lead to symptoms of schizophrenia, making these proteins attractive targets for possible treatments for the disorder. However, results from clinical trials of molecules used to boost NMDA receptor activity have been mixed. There is the additional concern that overstimulating NMDA receptors can cause neurons to die or can interfere with the connections between neurons.

One potential fix for this issue is to target a specific subtype of NMDA receptors whose activation is not thought to lead to such problems. These receptors contain a particular subunit called GluN2A, and a new study reports the discovery of compounds that can selectively bind to these receptors. The study, which was conducted by Jesse Hanson and colleagues at Genentech and was published online in Neuron on Feb. 11, shows that these compounds, called positive allosteric modulators (PAMs), interact with a newly identified modulatory site at the interface between GluN2A and another subunit, GluN1. Interestingly, different PAMs appear to have different effects on the behavior of the receptors as well as on the plasticity of connections between neurons that contain the receptors.

While these compounds don't have the appropriate properties to be used in animals or humans, their experimental use may provide a new way to probe the hypothesis that depressed NMDA receptor activity may be involved in the pathology of schizophrenia, and it is possible that other agents that target the same site may one day be developed as potential drugs for schizophrenia. "This [study] demonstrates this new way that wasn't possible before to enhance NMDA receptor function, which conceivably is a good thing according to some hypotheses of schizophrenia. But at this point, we're a long way from determining if this is safe or effective in any particular disease context," said Hanson. (For more details, see the related news story.)—Summer E. Allen.