- Email: [email protected]
Antidepressant Effects and Mechanisms of Group II mGlu Receptor-Specific Negative Allosteric Modulators
Neuron
Previews Antidepressant Effects and Mechanisms of Group II mGlu Receptor-Specific Negative Allosteric Modulators Liam E. Potter,1 Panos Zanos,1,2,3 and Todd D. Gould1,2,3,4,5,* 1Department
of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA 3Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA 4Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA 5Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.12.011 2Department
In this issue of Neuron, Joffe et al. (2020) assess the antidepressant-relevant effects and underlying neural mechanisms of negative allosteric modulators selective for either metabotropic glutamate receptors 2 (mGlu2) or 3 (mGlu3). Negative modulation of both receptors enhanced excitatory glutamatergic input to mouse prefrontal cortex pyramidal cells, leading to antidepressant-relevant actions. Historically, nearly all medications approved for the treatment of depression have targeted monoaminergic neurotransmission, inspiring monoamine-centric views of depression’s underlying neurobiology. These conventional antidepressant medications require long-term administration for an effect to emerge and leave a large proportion of individuals treatment resistant, continuing to suffer from depression. Over the last decade, the intravenous infusion of (R,S)-ketamine (ketamine) has been used as an off-label treatment for depression. Ketamine acts as an antidepressant within hours following a single administration in humans, and its effects following such an administration are typically sustained for days and sometimes up to a week. In March 2019, the United States Food and Drug Administration (FDA) approved (S)-ketamine (esketamine/Spravato) nasal spray for depression, constituting the first mechanistically novel antidepressant medication to be FDA sanctioned in several decades. A revised neurobiological understanding of depression places an emphasis on excitatory (glutamatergic) synaptic neurotransmission in specific mood- and reward-related neural circuits, including those that target or are targeted by the prefrontal cortex (PFC). Evidence indicates that synapses within these circuits are weakened by genetic and environmental factors, including exposure to chronic stress and/or circulating stress hormones (Duman et al., 2019; Gould
et al., 2019), which are linked to the development of depression in susceptible individuals (Figure 1A). Clinical and preclinical studies have shown that ketamine rapidly enhances glutamatergic neurotransmission in the PFC, as well as other regions including the hippocampus, and this synaptic plasticity is currently thought to underlie its rapid antidepressant effects (Duman et al., 2019; Gould et al., 2019) (Figure 1A). Although ketamine’s (and esketamine’s) rapid onset of action represents a significant advancement over conventional antidepressants, it also exhibits side effects that limit its widespread use, namely dissociation, and ketamine is also an abused drug. One alternative target being pursued are the group II metabotropic glutamate (mGlu) receptors comprised of mGlu2 and mGlu3, which both mediate negative feedback at glutamatergic synapses. Activation of these receptors suppresses synaptic glutamate release (mGlu2) or enhances glutamate reuptake and decreases postsynaptic glutamate signaling (mGlu3) (Ionescu and Papakostas, 2017) (Figure 1). It was previously determined that the mechanism underlying antidepressantrelevant actions of ketamine converges with mGlu2 signaling (Zanos et al., 2019), and orthosteric antagonists of group II mGlu exert rapid antidepressant-like effects in preclinical studies (Chaki, 2017). However, the specific contributions of mGlu2 and mGlu3 to these antidepressant actions were unknown.
The Conn group at Vanderbilt University had previously developed specific smallmolecule negative allosteric modulators (NAMs) of mGlu2 (VU6001966) and mGlu3 (VU0650786). In this issue of Neuron, Joffe et al. (2020) report on the rapid antidepressant effects of these NAMs and their possible mechanisms to exert antidepressant actions. The rationale was that such studies would clarify whether the antidepressant signal from non-selective group II mGlu inhibition arose primarily from mGlu2 versus mGlu3. The authors found that a single administration of either mGlu2- or mGlu3-specific NAMs acutely reduced passive coping behaviors (immobility) in a mouse test for antidepressant efficacy, the forced-swim test, and exerted anti-anhedonic effects following chronic stress that was sustained 24 h after drug administration. These latter findings are indicative of rapid-acting antidepressantlike responses of both compounds, similar to the sustained behavioral actions of ketamine (Duman et al., 2019; Gould et al., 2019). Based on previous studies (Fukumoto et al., 2016) that demonstrated that increased glutamate transmission in the PFC is necessary for the antidepressantlike effects of an orthosteric mixedmGlu2/3 antagonist, Joffe et al. (2020) examined neuronal activation in the PFC following systemic administration of the mGlu-specific NAMs. By using a mouse line that reports neuronal activity (FoseGFP), the authors found that both
Neuron 105, January 8, 2020 Published by Elsevier Inc. 1
Neuron
Previews
Figure 1. Convergent Roles of mGlu2 and mGlu3 Signaling in Depression Treatment (A) A combination of genetic and environmental factors contributes to decreased prefrontal glutamate signaling and depression symptoms (left). Rapid-acting antidepressant treatments, such as ketamine, are proposed to reverse this decrease in prefrontal glutamate signaling, leading to rapid and sustained relief of symptoms (right). (B) Schematic diagram of the mediodorsal thalamus to the prefrontal cortex neural pathway assessed by Joffe et al. (2020). (C) Schematic diagram of the synaptic mechanisms targeted by mGlu2- and mGlu3-specific NAMs (VU966 and VU786, respectively). Presynaptic mGlu2 acts as an inhibitory autoreceptor to restrain vesicular glutamate release. mGlu2-specific NAMs enhance glutamate release by attenuating this inhibitory feedback mechanism. mGlu3 located postsynaptically mediates long-term depression through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor downregulation. mGlu3-specific NAMs enhance glutamatergic signaling by attenuating this form of postsynaptic plasticity. mGlu3 is also found on astrocytes, and its activation enhances synaptic glutamate reuptake; however, an interaction between astrocytic mGlu3 and mGlu3-specific NAMs is not tested for in the current study. Abbreviations are as follows: BDNF, brain-derived neurotrophic factor; EAAT1/2, excitatory amino acid transporter 1 and 2; mTOR, mechanistic target of rapamycin kinase; NMDA, N-methyl-D-aspartate; VU6001966, VU966; and VU0650786, VU786.
mGlu2- and mGlu3-specific NAMs induce activation of a subpopulation of neurons within the PFC, referred to as ‘‘type A’’ (Anastasiades et al., 2018). A previous study found that type A neurons in the PFC are strongly and reciprocally connected with the mediodorsal thalamus (MDT) (Collins et al., 2018) (Figure 1B). Here, the experiments of Joffe et al. (2020) revealed that bath application of the mGlu2-specific NAM acutely augments optogenetically evoked MDT to PFC currents via a presynaptically targeted action to enhance glutamate release, suggesting that tonic activation of mGlu2 restrains 2 Neuron 105, January 8, 2020
glutamate release in this pathway (Figure 1C). In contrast, application of the mGlu3-specific NAM did not acutely modify MDT to PFC synaptic transmission, which appears to contradict the neuronal activation within the PFC observed following administration of the mGlu3 NAM in vivo. The authors addressed this discrepancy by demonstrating that both mGlu-specific NAMs attenuate mGlu3 activation-induced long-term depression (LTD) of synaptic strength in the MDT-to-PFC pathway (Figure 1C). The authors did not, however, test whether tonic mGlu3 activation-mediated LTD occurs at these synapses in vivo
or whether it is expressed following chronic stress, to further confirm that this is the mechanism underlying the observed mGlu3 NAM actions. This is an important question to be addressed in future studies. To establish a causal role for the actions of mGlu-specific NAMs on the MDT-toPFC circuit relevant to their observed antidepressant-like behavioral effects, the authors also tested mice in the forced swim test following chemogenetic inhibition of this circuit after acute drug treatment. While this manipulation was found to occlude the effects of mGlu NAM treatment on latency to immobility, chemogenetic
Neuron
Previews inhibition of the MDT-PFC pathway itself tended to increase latency to immobility in the absence of any NAM treatment, somewhat confounding an interpretation of these experimental results. In contrast with these findings, previous reports found that activation, rather than inhibition, of this circuit produces antidepressant-like effects (Miller et al., 2017). As the authors note, this contradictory finding could be explained by a net disinhibition of excitatory neurons in the PFC following chemogenetic inhibition because of the presence of extensive connections between the MDT and fast-spiking inhibitory cortical neurons. In order to avoid this confounding factor, future experiments could test the effect of MDT-PFC inhibition during the time of drug treatment and behaviorally test mice at a later time point. Such an experiment would be predicted to reveal a blockade of the persistent behavioral effects of mGlu2 and mGlu3 NAMs, given that transient activation of these neuronal ensembles during treatment is presumably necessary for the initiation of sustained synaptic plasticity. Additionally, since it has been established that the persistent antidepressant-like effects of mixed mGlu2/3 antagonists require downstream factors shared with other rapid-acting antidepressants (e.g., brain-derived neurotrophic factor [BDNF] and mechanistic target of rapamycin kinase [mTOR] signaling; Chaki, 2017; Duman et al., 2019; Gould et al., 2019), the role of these pathways could be examined in future studies by using mGlu-specific NAMs. mGlu receptors represent an enticing target in the search for novel rapid-acting antidepressants, given their proximity to and function at synapses altered in depression. This paper provides the first
evidence suggesting that both mGlu2 and mGlu3 inhibition may individually have rapid-acting antidepressant effects, similar to ketamine. To date, only one drug targeting group II mGlu receptors for depression has been assessed in a clinical trial. In particular, in a phase 2 clinical trial, administration of decoglurant, a mixed mGlu2/3 negative allosteric modulator, did not differentiate from a placebo in patients suffering from depression (Gould et al., 2019). However, since no marker of target engagement was assessed, it is difficult to confirm that adequate brain exposure was achieved, and thus, further clinical studies are required to assess for the antidepressant actions of mGlu2 or mGlu3 inhibition, either in combination or individually. Although there continues to be a lack of clarity regarding whether inhibition of mGlu2, mGlu3, or both receptors together is the most viable approach to antidepressant action, the ability to separately target mGlu2 and mGlu3 using specific NAMs presents the potential for a more focused treatment of depression. In summary, these group II mGlu NAMs, or molecules with similar pharmacology, represent promising candidates as novel rapid-acting antidepressants.
DECLARATION OF INTERESTS T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7 LLC during the preceding three years. P.Z. and T.D.G. are co-inventors in patent applications related to the pharmacology and synthesis, crystal structure, and use of ketamine metabolites (2R,6R)-HNK in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. L.E.P. declares no competing interests.
REFERENCES Anastasiades, P.G., Marlin, J.J., and Carter, A.G. (2018). Cell-Type Specificity of Callosally Evoked Excitation and Feedforward Inhibition in the Prefrontal Cortex. Cell Rep. 22, 679–692. Chaki, S. (2017). mGlu2/3 Receptor Antagonists as Novel Antidepressants. Trends Pharmacol. Sci. 38, 569–580. Collins, D.P., Anastasiades, P.G., Marlin, J.J., and Carter, A.G. (2018). Reciprocal Circuits Linking the Prefrontal Cortex with Dorsal and Ventral Thalamic Nuclei. Neuron 98, 366–379.e4. Duman, R.S., Sanacora, G., and Krystal, J.H. (2019). Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron 102, 75–90. Fukumoto, K., Iijima, M., and Chaki, S. (2016). The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN. Neuropsychopharmacology 41, 1046–1056. Gould, T.D., Zarate, C.A., Jr., and Thompson, S.M. (2019). Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants. Annu. Rev. Pharmacol. Toxicol. 59, 213–236. Ionescu, D.F., and Papakostas, G.I. (2017). Experimental medication treatment approaches for depression. Transl. Psychiatry 7, e1068, e1068. Joffe, M.E., Santiago, C.I., Oliver, K.H., Maksymetz, J., Harris, N.A., Engers, J.L., Lindsley, C.W., Winder, D.G., and Conn, P.J. (2020). mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects. Neuron 105, this issue, 46–59. Miller, O.H., Bruns, A., Ben Ammar, I., Mueggler, T., and Hall, B.J. (2017). Synaptic Regulation of a Thalamocortical Circuit Controls DepressionRelated Behavior. Cell Rep. 20, 1867–1880. Zanos, P., Highland, J.N., Stewart, B.W., Georgiou, P., Jenne, C.E., Lovett, J., Morris, P.J., Thomas, C.J., Moaddel, R., Zarate, C.A., Jr., and Gould, T.D. (2019). (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proc. Natl. Acad. Sci. USA 116, 6441–6450.
Neuron 105, January 8, 2020 3
Previews Antidepressant Effects and Mechanisms of Group II mGlu Receptor-Specific Negative Allosteric Modulators Liam E. Potter,1 Panos Zanos,1,2,3 and Todd D. Gould1,2,3,4,5,* 1Department
of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA 3Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA 4Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA 5Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.12.011 2Department
In this issue of Neuron, Joffe et al. (2020) assess the antidepressant-relevant effects and underlying neural mechanisms of negative allosteric modulators selective for either metabotropic glutamate receptors 2 (mGlu2) or 3 (mGlu3). Negative modulation of both receptors enhanced excitatory glutamatergic input to mouse prefrontal cortex pyramidal cells, leading to antidepressant-relevant actions. Historically, nearly all medications approved for the treatment of depression have targeted monoaminergic neurotransmission, inspiring monoamine-centric views of depression’s underlying neurobiology. These conventional antidepressant medications require long-term administration for an effect to emerge and leave a large proportion of individuals treatment resistant, continuing to suffer from depression. Over the last decade, the intravenous infusion of (R,S)-ketamine (ketamine) has been used as an off-label treatment for depression. Ketamine acts as an antidepressant within hours following a single administration in humans, and its effects following such an administration are typically sustained for days and sometimes up to a week. In March 2019, the United States Food and Drug Administration (FDA) approved (S)-ketamine (esketamine/Spravato) nasal spray for depression, constituting the first mechanistically novel antidepressant medication to be FDA sanctioned in several decades. A revised neurobiological understanding of depression places an emphasis on excitatory (glutamatergic) synaptic neurotransmission in specific mood- and reward-related neural circuits, including those that target or are targeted by the prefrontal cortex (PFC). Evidence indicates that synapses within these circuits are weakened by genetic and environmental factors, including exposure to chronic stress and/or circulating stress hormones (Duman et al., 2019; Gould
et al., 2019), which are linked to the development of depression in susceptible individuals (Figure 1A). Clinical and preclinical studies have shown that ketamine rapidly enhances glutamatergic neurotransmission in the PFC, as well as other regions including the hippocampus, and this synaptic plasticity is currently thought to underlie its rapid antidepressant effects (Duman et al., 2019; Gould et al., 2019) (Figure 1A). Although ketamine’s (and esketamine’s) rapid onset of action represents a significant advancement over conventional antidepressants, it also exhibits side effects that limit its widespread use, namely dissociation, and ketamine is also an abused drug. One alternative target being pursued are the group II metabotropic glutamate (mGlu) receptors comprised of mGlu2 and mGlu3, which both mediate negative feedback at glutamatergic synapses. Activation of these receptors suppresses synaptic glutamate release (mGlu2) or enhances glutamate reuptake and decreases postsynaptic glutamate signaling (mGlu3) (Ionescu and Papakostas, 2017) (Figure 1). It was previously determined that the mechanism underlying antidepressantrelevant actions of ketamine converges with mGlu2 signaling (Zanos et al., 2019), and orthosteric antagonists of group II mGlu exert rapid antidepressant-like effects in preclinical studies (Chaki, 2017). However, the specific contributions of mGlu2 and mGlu3 to these antidepressant actions were unknown.
The Conn group at Vanderbilt University had previously developed specific smallmolecule negative allosteric modulators (NAMs) of mGlu2 (VU6001966) and mGlu3 (VU0650786). In this issue of Neuron, Joffe et al. (2020) report on the rapid antidepressant effects of these NAMs and their possible mechanisms to exert antidepressant actions. The rationale was that such studies would clarify whether the antidepressant signal from non-selective group II mGlu inhibition arose primarily from mGlu2 versus mGlu3. The authors found that a single administration of either mGlu2- or mGlu3-specific NAMs acutely reduced passive coping behaviors (immobility) in a mouse test for antidepressant efficacy, the forced-swim test, and exerted anti-anhedonic effects following chronic stress that was sustained 24 h after drug administration. These latter findings are indicative of rapid-acting antidepressantlike responses of both compounds, similar to the sustained behavioral actions of ketamine (Duman et al., 2019; Gould et al., 2019). Based on previous studies (Fukumoto et al., 2016) that demonstrated that increased glutamate transmission in the PFC is necessary for the antidepressantlike effects of an orthosteric mixedmGlu2/3 antagonist, Joffe et al. (2020) examined neuronal activation in the PFC following systemic administration of the mGlu-specific NAMs. By using a mouse line that reports neuronal activity (FoseGFP), the authors found that both
Neuron 105, January 8, 2020 Published by Elsevier Inc. 1
Neuron
Previews
Figure 1. Convergent Roles of mGlu2 and mGlu3 Signaling in Depression Treatment (A) A combination of genetic and environmental factors contributes to decreased prefrontal glutamate signaling and depression symptoms (left). Rapid-acting antidepressant treatments, such as ketamine, are proposed to reverse this decrease in prefrontal glutamate signaling, leading to rapid and sustained relief of symptoms (right). (B) Schematic diagram of the mediodorsal thalamus to the prefrontal cortex neural pathway assessed by Joffe et al. (2020). (C) Schematic diagram of the synaptic mechanisms targeted by mGlu2- and mGlu3-specific NAMs (VU966 and VU786, respectively). Presynaptic mGlu2 acts as an inhibitory autoreceptor to restrain vesicular glutamate release. mGlu2-specific NAMs enhance glutamate release by attenuating this inhibitory feedback mechanism. mGlu3 located postsynaptically mediates long-term depression through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor downregulation. mGlu3-specific NAMs enhance glutamatergic signaling by attenuating this form of postsynaptic plasticity. mGlu3 is also found on astrocytes, and its activation enhances synaptic glutamate reuptake; however, an interaction between astrocytic mGlu3 and mGlu3-specific NAMs is not tested for in the current study. Abbreviations are as follows: BDNF, brain-derived neurotrophic factor; EAAT1/2, excitatory amino acid transporter 1 and 2; mTOR, mechanistic target of rapamycin kinase; NMDA, N-methyl-D-aspartate; VU6001966, VU966; and VU0650786, VU786.
mGlu2- and mGlu3-specific NAMs induce activation of a subpopulation of neurons within the PFC, referred to as ‘‘type A’’ (Anastasiades et al., 2018). A previous study found that type A neurons in the PFC are strongly and reciprocally connected with the mediodorsal thalamus (MDT) (Collins et al., 2018) (Figure 1B). Here, the experiments of Joffe et al. (2020) revealed that bath application of the mGlu2-specific NAM acutely augments optogenetically evoked MDT to PFC currents via a presynaptically targeted action to enhance glutamate release, suggesting that tonic activation of mGlu2 restrains 2 Neuron 105, January 8, 2020
glutamate release in this pathway (Figure 1C). In contrast, application of the mGlu3-specific NAM did not acutely modify MDT to PFC synaptic transmission, which appears to contradict the neuronal activation within the PFC observed following administration of the mGlu3 NAM in vivo. The authors addressed this discrepancy by demonstrating that both mGlu-specific NAMs attenuate mGlu3 activation-induced long-term depression (LTD) of synaptic strength in the MDT-to-PFC pathway (Figure 1C). The authors did not, however, test whether tonic mGlu3 activation-mediated LTD occurs at these synapses in vivo
or whether it is expressed following chronic stress, to further confirm that this is the mechanism underlying the observed mGlu3 NAM actions. This is an important question to be addressed in future studies. To establish a causal role for the actions of mGlu-specific NAMs on the MDT-toPFC circuit relevant to their observed antidepressant-like behavioral effects, the authors also tested mice in the forced swim test following chemogenetic inhibition of this circuit after acute drug treatment. While this manipulation was found to occlude the effects of mGlu NAM treatment on latency to immobility, chemogenetic
Neuron
Previews inhibition of the MDT-PFC pathway itself tended to increase latency to immobility in the absence of any NAM treatment, somewhat confounding an interpretation of these experimental results. In contrast with these findings, previous reports found that activation, rather than inhibition, of this circuit produces antidepressant-like effects (Miller et al., 2017). As the authors note, this contradictory finding could be explained by a net disinhibition of excitatory neurons in the PFC following chemogenetic inhibition because of the presence of extensive connections between the MDT and fast-spiking inhibitory cortical neurons. In order to avoid this confounding factor, future experiments could test the effect of MDT-PFC inhibition during the time of drug treatment and behaviorally test mice at a later time point. Such an experiment would be predicted to reveal a blockade of the persistent behavioral effects of mGlu2 and mGlu3 NAMs, given that transient activation of these neuronal ensembles during treatment is presumably necessary for the initiation of sustained synaptic plasticity. Additionally, since it has been established that the persistent antidepressant-like effects of mixed mGlu2/3 antagonists require downstream factors shared with other rapid-acting antidepressants (e.g., brain-derived neurotrophic factor [BDNF] and mechanistic target of rapamycin kinase [mTOR] signaling; Chaki, 2017; Duman et al., 2019; Gould et al., 2019), the role of these pathways could be examined in future studies by using mGlu-specific NAMs. mGlu receptors represent an enticing target in the search for novel rapid-acting antidepressants, given their proximity to and function at synapses altered in depression. This paper provides the first
evidence suggesting that both mGlu2 and mGlu3 inhibition may individually have rapid-acting antidepressant effects, similar to ketamine. To date, only one drug targeting group II mGlu receptors for depression has been assessed in a clinical trial. In particular, in a phase 2 clinical trial, administration of decoglurant, a mixed mGlu2/3 negative allosteric modulator, did not differentiate from a placebo in patients suffering from depression (Gould et al., 2019). However, since no marker of target engagement was assessed, it is difficult to confirm that adequate brain exposure was achieved, and thus, further clinical studies are required to assess for the antidepressant actions of mGlu2 or mGlu3 inhibition, either in combination or individually. Although there continues to be a lack of clarity regarding whether inhibition of mGlu2, mGlu3, or both receptors together is the most viable approach to antidepressant action, the ability to separately target mGlu2 and mGlu3 using specific NAMs presents the potential for a more focused treatment of depression. In summary, these group II mGlu NAMs, or molecules with similar pharmacology, represent promising candidates as novel rapid-acting antidepressants.
DECLARATION OF INTERESTS T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7 LLC during the preceding three years. P.Z. and T.D.G. are co-inventors in patent applications related to the pharmacology and synthesis, crystal structure, and use of ketamine metabolites (2R,6R)-HNK in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. L.E.P. declares no competing interests.
REFERENCES Anastasiades, P.G., Marlin, J.J., and Carter, A.G. (2018). Cell-Type Specificity of Callosally Evoked Excitation and Feedforward Inhibition in the Prefrontal Cortex. Cell Rep. 22, 679–692. Chaki, S. (2017). mGlu2/3 Receptor Antagonists as Novel Antidepressants. Trends Pharmacol. Sci. 38, 569–580. Collins, D.P., Anastasiades, P.G., Marlin, J.J., and Carter, A.G. (2018). Reciprocal Circuits Linking the Prefrontal Cortex with Dorsal and Ventral Thalamic Nuclei. Neuron 98, 366–379.e4. Duman, R.S., Sanacora, G., and Krystal, J.H. (2019). Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron 102, 75–90. Fukumoto, K., Iijima, M., and Chaki, S. (2016). The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN. Neuropsychopharmacology 41, 1046–1056. Gould, T.D., Zarate, C.A., Jr., and Thompson, S.M. (2019). Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants. Annu. Rev. Pharmacol. Toxicol. 59, 213–236. Ionescu, D.F., and Papakostas, G.I. (2017). Experimental medication treatment approaches for depression. Transl. Psychiatry 7, e1068, e1068. Joffe, M.E., Santiago, C.I., Oliver, K.H., Maksymetz, J., Harris, N.A., Engers, J.L., Lindsley, C.W., Winder, D.G., and Conn, P.J. (2020). mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects. Neuron 105, this issue, 46–59. Miller, O.H., Bruns, A., Ben Ammar, I., Mueggler, T., and Hall, B.J. (2017). Synaptic Regulation of a Thalamocortical Circuit Controls DepressionRelated Behavior. Cell Rep. 20, 1867–1880. Zanos, P., Highland, J.N., Stewart, B.W., Georgiou, P., Jenne, C.E., Lovett, J., Morris, P.J., Thomas, C.J., Moaddel, R., Zarate, C.A., Jr., and Gould, T.D. (2019). (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proc. Natl. Acad. Sci. USA 116, 6441–6450.
Neuron 105, January 8, 2020 3