Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

Matosin, Natalie; Fernandez, Francesca; Frank, Elisabeth; Deng, Chao; Wong, Jenny; Huang, Xu‐Feng; Newell, Kelly A.

doi:10.1503/jpn.130242

Cited by 61 publications

(40 citation statements)

References 45 publications

(75 reference statements)

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“…In particular, these receptors have been implicated as important in various neurological disorders, such as schizophrenia, and their appearance in these regions may hint at their crucial role for the proper functioning of these circuits [7] [19] [27]. Alternatively, their combined expression in these regions in the developing brain may act as a molecular signal for the development of these circuits in the mature brain [28] [29].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of mGluR2 in the Developing Cerebral Cortex of the Mouse

Venkatadri

Lee

2014

JBiSE

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Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distributed on neurons throughout the central nervous system. These receptors are broadly classified into two main groups, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). Unlike iGluRs, the mGluRs are G-protein coupled receptors that exert their effects on postsynaptic membrane conductance indirectly through the downstream modification of ion channels. A subtype of mGluRs, the Group II mGluRs, are particularly interesting since their activation by glutamate results in a hyperpolarizing response. Thus, glutamate can act potentially as an inhibitory neurotransmitter, by binding to postsynaptic Group II mGluRs. Given the potential importance of these receptors in synaptic processing, the development of the central nervous system, and neurological disorders, we sought to characterize the expression of mGluR2 in the developing neocortex of the mouse. Therefore, we examined the distribution of mGluR2 in the developing cerebral cortex. We found a general caudal to rostral gradient in the expression of these receptors, with ventral cortical regions labeled caudally and dorsal regions labeled rostrally. Limbic regions highly expressed mGluR2 throughout the brain, as did sensory and motor cortical areas. Finally, other non-cortical structures, such as the thalamic reticular nucleus, amygdala, and mammillary bodies were found to have significant expression of the receptor. These results suggest that mGluR2 may play important roles in mediating glutamatergic inhibition in these structures and also could have a role in shaping the development of mature neural networks in the forebrain.

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Section: Discussionmentioning

confidence: 99%

Differential Expression of mGluR2 in the Developing Cerebral Cortex of the Mouse

Venkatadri

Lee

2014

JBiSE

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“…not active in patients suffering from schizophrenia (61). On the other hand, antagonists and NAMs of mGluR2/3 have potential antidepressant efficacy (62). In order to explore the selectivity of mGluR2/3 and compare the different binding residues between NAM and PAM, we built the homology models of mGluR2/3 on the basis of the crystal structure of mGluR5 (Table S1), and performed the dockings with existing ligands (a highly selective mGluR2 PAM, an analog of BINA (57); a nonselective mGluR2/3 NAM, RO-4491533(58)).…”

Section: Mglur1 Bound With Selective Negative Allosteric Modulatorsmentioning

confidence: 99%

Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

Feng

et al. 2015

AAPS J

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Abstract. Metabotropic glutamate receptors (mGluR) are mainly expressed in the central nervous system (CNS) and contain eight receptor subtypes, named mGluR1 to mGluR8. The crystal structures of mGluR1 and mGluR5 that are bound with the negative allosteric modulator (NAM) were reported recently. These structures provide a basic model for all class C of G-protein coupled receptors (GPCRs) and may aid in the design of new allosteric modulators for the treatment of CNS disorders. However, these structures are only combined with NAMs in the previous reports. The conformations that are bound with positive allosteric modulator (PAM) or agonist of mGluR1/5 remain unknown. Moreover, the structural information of the other six mGluRs and the comparisons of the mGluRs family have not been explored in terms of their binding pockets, the binding modes of different compounds, and important binding residues. With these crystal structures as the starting point, we built 3D structural models for six mGluRs by using homology modeling and molecular dynamics (MD) simulations. We systematically compared their allosteric binding sites/pockets, the important residues, and the selective residues by using a series of comparable dockings with both the NAM and the PAM. Our results show that several residues played important roles for the receptors' selectivity. The observations of detailed interactions between compounds and their correspondent receptors are congruent with the specificity and potency of derivatives or compounds bioassayed in vitro. We then carried out 100 ns MD simulations of mGluR5 (residue 26-832, formed by Venus Flytrap domain, a so-called cysteine-rich domain, and 7 transmembrane domains) bound with antagonist/NAM and with agonist/PAM. Our results show that both the NAM and the PAM seemed stable in class C GPCRs during the MD. However, the movements of Bionic lock,^of trans-membrane domains, and of some activation-related residues in 7 trans-membrane domains of mGluR5 were congruent with the findings in class A GPCRs. Finally, we selected nine representative bound structures to perform 30 ns MD simulations for validating the stabilities of interactions, respectively. All these bound structures kept stable during the MD simulations, indicating that the binding poses in this present work are reasonable. We provided new insight into better understanding of the structural and functional roles of the mGluRs family and facilitated the future structure-based design of novel ligands of mGluRs family with therapeutic potential.

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“…The expression of mGluR2/3 in cortical regions appears to vary between populations of patients, with reduced (Corti et al, 2007;Ghose et al, 2009;González-Maeso et al, 2008;Gupta et al, 2005) and unchanged levels being reported (Frank et al, 2011;Matosin et al, 2014). In accordance, increasing the activity of mGluR2/3 receptors might therefore be a viable treatment strategy.…”

Section: The Mglur2/3 Agonist Ly379268 Restores Nmda-r and Gabaa-r Exmentioning

confidence: 96%

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

et al. 2016

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Rationale An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. Objectives We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-daspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a twohit mouse model of schizophrenia. Methods Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. Results In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. Conclusions We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. Disciplines Medicine and Health Sciences Publication DetailsEngel, M., Snikeris, P., Matosin, N., Newell, K. Anne., Huang, X. & Frank, E. (2016). mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia. Psychopharmacology, 233 (8) AcknowledgmentsThis work was supported by the Schizophrenia Research Institute, utilising infrastructure funding from the NSW Ministry of Health. LY379268 was kindly gifted by Eli Lilly & Co (Indianapolis, USA). The funding bodies had no role in the study design, data collection and publication decisions. 2 AbstractRationale An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of Group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.Objectives We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.Me...

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Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

Cited by 61 publications

References 45 publications

Differential Expression of mGluR2 in the Developing Cerebral Cortex of the Mouse

Differential Expression of mGluR2 in the Developing Cerebral Cortex of the Mouse

Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

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