The rapid and robust antidepressant efficacy of ketamine has broken the decades-long impasse in developing improved pharmacological approaches for the treatment of depression. However, adverse effects and other limitations have created a difficult path to ketamine’s widespread clinical utility, stimulating intense efforts to develop alternative treatments that act through similar biological mechanisms. In animal models, ketamine disinhibits the prefrontal cortex (PFC), promoting activity of excitatory synapses subjected to damage or atrophy during chronic stress . Two alternative antidepressant targets are metabotropic glutamate (mGlu) receptors mGlu2 and mGlu3, related receptors that commonly couple with Gi/o protein signaling and attenuate synaptic transmission . mGlu2 and mGlu3 are localized at presynaptic terminals throughout the central nervous system, however, mGlu3 is also expressed flanking postsynaptic sites and on astrocytes. Non-selective mGlu2/3 antagonists enhance glutamatergic transmission in the PFC and, consistent with that mechanism, exert rapid antidepressant-like effects in several preclinical models .
The roles of the individual mGlu receptor subtypes in modulating PFC transmission and inducing antidepressant-like effects remain unclear. Most mGlu2/3 ligands do not discriminate between receptors, but in recent years, highly selective and systemically active negative allosteric modulators (NAMs) for both mGlu2 and mGlu3 have been developed [4, 5]. Now, using these compounds, several exciting discoveries advance our understanding of how mGlu2 and mGlu3 regulate PFC transmission and related behaviors. In the PFC, mGlu2 modulates presynaptic glutamate release probability, whereas postsynaptic mGlu3 regulates the internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in pyramidal cells . The latter plasticity is impaired by acute stress and mGlu3 NAMs can restore normal physiology and motivation. Studies using optogenetics have revealed that mGlu2 and mGlu3 function differentially across distinct long-range excitatory inputs to the PFC. These findings suggest NAMs for either mGlu2 or mGlu3 may preferentially alter amygdalo–PFC transmission without affecting inputs from the hippocampus. Furthermore, unlike ketamine and other experimental antidepressants that suppress interneuron activity, mGlu2 and mGlu3 do not directly modulate PFC inhibitory transmission. Taken together, these circuit-specific findings suggest that mGlu2 and mGlu3 NAMs may provide a means to redirect limbic system afferents to the PFC while sparing the local microcircuitry from gross disruption. This approach could be superior for patients with likely deficits in interneuron function, such as those with comorbid psychotic or cognitive symptoms. To that point, ketamine induces psychotomimetic effects, while minimal evidence suggests similar liability for mGlu2 or mGlu3 NAMs.
In addition to these mechanistic lines of research, recent studies have shown that selective inhibition of mGlu3, but not mGlu2, decreases immobility in the tail suspension test, a preclinical assay for antidepressant-like activity . At face value, this finding may dampen enthusiasm for the translation of mGlu2 NAMs as novel antidepressants, but tests of behavioral despair are biased to identify monoaminergic mechanisms. Further studies in etiologically relevant animal models are therefore warranted to assess the efficacy of mGlu2 and mGlu3 NAMs in treating anhedonia. Exciting data presented at recent meetings demonstrate that both mGlu2 and mGlu3 NAMs rapidly reverse deficits in sucrose preference induced by chronic stress, suggesting that mGlu2 and mGlu3 NAMs may provide a means to confer faster symptom relief compared with available antidepressants. With new selective compounds and sophisticated genetic models, it will be possible to systematically test this hypothesis and fully evaluate the roles for both receptor subtypes.
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We would like to acknowledge Drs. Darryle Schoepp, Shigeyuki Chaki and Ronald Duman, for their work evaluating the preclinical antidepressant-like effects of mGlu2/3 antagonists. MEJ was supported by a postdoctoral fellowship through the Pharmaceutical Research and Manufacturers of America Foundation. PJC was supported by National Institutes of Health (NIH) grants R01MH062646 and R37NS031373. PJC has been funded by NIH, AstraZeneca, Bristol-Myers Squibb, Michael J. Fox Foundation, Dystonia Medical Research Foundation, CHDI Foundation and Thome Memorial Foundation. Over the past 3 years, he has served on the Scientific Advisory Boards for Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute, Karuna Pharmaceuticals, Lieber Institute for Brain Development, Clinical Mechanism and Proof of Concept Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder.
PJC is an inventor on patents that protect different classes of metabotropic glutamate allosteric modulators and MEJ declares no competing interests.
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Joffe, M.E., Conn, P.J. Antidepressant potential of metabotropic glutamate receptor mGlu2 and mGlu3 negative allosteric modulators. Neuropsychopharmacol 44, 214–236 (2019). https://doi.org/10.1038/s41386-018-0192-8
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