Dr. Joshua Levitz, study senior author, associate professor of biochemistry at Weill Cornell Medicine
Researchers at Weill Cornell Medicine have made a significant breakthrough in understanding how drugs that target the mGluR2 receptor can reduce anxiety. Their innovative toolkit provides valuable insights into the specific neural circuits responsible for anxiety relief, paving the way for more targeted and effective anxiety medications with fewer side effects.
Understanding mGluR2 and Anxiety
The mGluR2 receptor, often described as a “dimmer switch” for synaptic transmission, has shown promise in reducing anxiety in preclinical and limited clinical studies. However, the development of drugs targeting this receptor has been hindered by potential side effects. mGluR2 is present in various brain circuits, and drugs that activate mGluR2 often inadvertently activate other receptors, leading to unwanted consequences.
New Insights with a Circuit-Specific Tool
Dr. Joshua Levitz and his team have developed a new method to map the effects of drugs on specific neural circuits. They discovered that the basal lateral amygdala (BLA) is a key region where mGluR2 activators exert their anxiolytic effects. By using genetic tools and a specialized virus tracer, they identified two circuits in the BLA that express high levels of mGluR2 and are linked to anxiety in mice.
Photopharmacology Unveiled
Dr. Levitz introduced a photopharmacology technique he developed in the early 2010s. This method uses light-sensitive molecules tethered to mGluR2, enabling researchers to activate the receptor in specific brain circuits. In their study, they found that stimulating mGluR2 in a circuit connecting the ventromedial prefrontal cortex to the BLA reduced spatial avoidance, a common anxiety indicator in mice. However, this reduction was accompanied by memory impairment, suggesting that cognitive side effects may be a common issue with current anxiety drugs.
“This working memory deficit we observed may be a basis for the cognitive impairment associated with typical anxiety drugs,” Dr. Levitz explained.
Future Directions and Implications
The research team is now working on selective targeting of these circuits without relying on mGluR2 activation. This approach could potentially develop medications with fewer side effects. Dr. Levitz and his colleagues are also applying their new toolkit to study other drug classes, including opioids and antidepressants, which could have widespread applications in neuroscience and psychiatry.
Significance and Impact
This breakthrough highlights the importance of understanding specific neural pathways in drug development. By identifying the exact circuits responsible for anxiety relief, researchers can design more targeted treatments with a higher margin of safety. This could ultimately improve the quality of life for millions of people suffering from anxiety disorders.
Source:
Journal reference:
Munguba, H., et al. (2025) Projection-targeted photopharmacology reveals distinct anxiolytic roles for presynaptic mGluR2 in prefrontal- and insula-amygdala synapses. Neuron. doi.org/10.1016/j.neuron.2025.01.002.
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