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Optogenetic Manipulation of Neuronal Activity to Modulate Behavior in Freely Moving Mice
Published on: October 27, 2020
Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala
Christine E Gee1, Daniel Peterlik2, Christoph Neuhäuser2
1Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland,; Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, D-20249 Hamburg, Germany.
Abstract:
The metabotropic glutamate receptor subtype 7 (mGlu7) is an important presynaptic regulator of neurotransmission in the mammalian CNS. mGlu7 function has been linked to autism, drug abuse, anxiety, and depression. Despite this, it has been difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as amygdala and limbic cortex. Here, we present the mGlu7-selective antagonist 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), which inhibits lateral amygdala long term potentiation (LTP) in brain slices from wild type mice with a half-maximal blockade at 88 nm. There was no effect of XAP044 on LTP of mGlu7-deficient mice, indicating that this pharmacological effect is mGlu7-dependent. Unexpectedly and in contrast to all previous mGlu7-selective drugs, XAP044 does not act via the seven-transmembrane region but rather via a binding pocket localized in mGlu7's extracellular Venus flytrap domain, a region generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. XAP044 demonstrates good brain exposure and wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy in rodent behavioral paradigms. XAP044 reduces freezing during acquisition of Pavlovian fear and reduces innate anxiety, which is consistent with the phenotypes of mGlu7-deficient mice, the results of mGlu7 siRNA knockdown studies, and the inhibition of amygdala LTP by XAP044. Thus, we present an mGlu7 antagonist with a novel molecular mode of pharmacological action, providing significant application potential in psychiatry. Modeling the selective interaction between XAP044 and mGlu7's Venus flytrap domain, whose three-dimensional structure is already known, will facilitate future drug development supported by computer-assisted drug design.
Insights
A novel metabotropic glutamate receptor subtype 7 (mGlu7) antagonist, XAP044, effectively reduces anxiety and depression-like behaviors in rodents. This compound targets the Venus flytrap domain, offering a new therapeutic avenue for psychiatric disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Metabotropic glutamate receptor subtype 7 (mGlu7) is a key regulator of neurotransmission in the central nervous system.
- mGlu7 dysfunction is implicated in various psychiatric conditions, including anxiety, depression, autism, and drug abuse.
- Developing selective mGlu7 antagonists has been challenging due to difficulties in targeting native signaling in critical brain regions.
Purpose of the Study:
- To introduce a novel, selective antagonist for mGlu7, named XAP044.
- To characterize the pharmacological profile and mechanism of action of XAP044.
- To evaluate the efficacy of XAP044 in preclinical models of anxiety and depression.
Main Methods:
- Electrophysiological recordings of long-term potentiation (LTP) in mouse brain slices.
- Chimeric receptor studies in recombinant cell line assays to determine the binding site.
- Behavioral paradigms in rodents to assess anti-stress, antidepressant, and anxiolytic-like effects.
Main Results:
- XAP044 selectively inhibited mGlu7-dependent LTP in the lateral amygdala with an IC50 of 88 nM.
- Unlike previous antagonists, XAP044 binds to the extracellular Venus flytrap domain of mGlu7, not the transmembrane region.
- XAP044 demonstrated significant anti-stress, antidepressant, and anxiolytic-like efficacy in rodent models, reducing freezing behavior and innate anxiety.
Conclusions:
- XAP044 is a potent and selective mGlu7 antagonist with a novel mechanism of action.
- The compound exhibits promising therapeutic potential for psychiatric disorders characterized by mGlu7 dysregulation.
- Targeting the Venus flytrap domain of mGlu7 represents a new strategy for drug development in psychiatry, potentially aided by computational modeling.
