mGlu Receptors Research Articles

Blunted type-5 metabotropic glutamate receptor-mediated polyphosphoinositide hydrolysis in two mouse models of monogenic autism

The involvement of the mGlu5 receptors in the pathophysiology of several forms of monogenic autism has been supported by numerous studies following the seminal observation that mGlu5 receptor-dependent long-term depression was enhanced in the hippocampus of mice modeling the fragile-X syndrome (FXS). Surprisingly, there are no studies examining the canonical signal transduction pathway activated by mGlu5 receptors (i.e. polyphosphoinositide – PI – hydrolysis) in mouse models of autism. We have developed a method for in vivo assessment of PI hydrolysis based on systemic injection of lithium chloride followed by treatment with the selective mGlu5 receptor PAM, VU0360172, and measurement of endogenous inositolmonophosphate (InsP) in brain tissue. Here, we report that mGlu5 receptor-mediated PI hydrolysis was blunted in the cerebral cortex, hippocampus, and corpus striatum of Ube3am−/p+ mice modeling Angelman syndrome (AS), and in the cerebral cortex and hippocampus of Fmr1 knockout mice modeling FXS. In vivo mGlu5 receptor-mediated stimulation of Akt on threonine 308 was also blunted in the hippocampus of FXS mice. These changes were associated with a significant increase in cortical and striatal Homer1 levels and striatal mGlu5 receptor and Gαq levels in AS mice, and with a reduction in cortical mGlu5 receptor and hippocampal Gαq levels, and an increase in cortical phospholipase-Cβ and hippocampal Homer1 levels in FXS mice.This is the first evidence that the canonical transduction pathway activated by mGlu5 receptors is down-regulated in brain regions of mice modeling monogenic autism.

Group I mGluRs positive allosteric modulators improved schizophrenia-related behavioral and molecular deficits in the Poly I:C rat model

RationaleMaternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. ObjectivesThe aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. MethodsFemale Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. ResultsPoly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. ConclusionsThese results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.

Concerted conformational changes control metabotropic glutamate receptor activity.

Allosteric modulators bear great potential to fine-tune neurotransmitter action. Promising targets are metabotropic glutamate (mGlu) receptors, which are associated with numerous brain diseases. Orthosteric and allosteric ligands act in synergy to control the activity of these multidomain dimeric GPCRs. Here, we analyzed the effect of such molecules on the concerted conformational changes of full-length mGlu2 at the single-molecule level. We first established FRET sensors through genetic code expansion combined with click chemistry to monitor conformational changes on live cells. We then used single-molecule FRET and show that orthosteric agonist binding leads to the stabilization of most of the glutamate binding domains in their closed state, while the reorientation of the dimer into the active state remains partial. Allosteric modulators, interacting with the transmembrane domain, are required to stabilize the fully reoriented active dimer. These results illustrate how concerted conformational changes within multidomain proteins control their activity, and how these are modulated by allosteric ligands.

Maternal diabetes decreases the expression of GABAAα1, GABAB1, and mGlu2 receptors in the visual cortex of male rat neonates

AimsThis study examines the impact of maternal diabetes on the expression of GABAB1, GABAAα1, and mGlu2 receptors in the primary visual cortex layers of male rat newborns.Main Methods: In diabetic group (Dia), diabetes was induced in adult female rats using an intraperitoneal dose of Streptozotocin (STZ) 65 (mg/kg). Diabetes was managed by daily subcutaneous injection of NPH insulin in insulin-treated diabetic group (Ins). Control group (Con) received normal saline intraperitoneally rather than STZ. Male offspring born to each group of female rats were euthanized via CO2 inhalation at P0, P7, and P14 days after delivery and the expression of GABAB1, GABAAα1, and mGlu2 receptors in their primary visual cortex was determined using immunohistochemistry (IHC).Key Findings: The expression of GABAB1, GABAAα1, and mGlu2 receptors increased gradually with age in the male offspring born to Con group while the highest expression was detected in layer IV of the primary visual cortex. In Dia group newborns, the expression of these receptors was significantly reduced in all layers of the primary visual cortex at every three days. Insulin treatment in diabetic mothers restored the expression of these receptors to normal levels in their newborns. SignificanceThe study indicates that diabetes reduces the expression of GABAB1, GABAAα1, and mGlu2 receptors in the primary visual cortex of male offspring born to diabetic rats at P0, P7, and P14. However, insulin treatment can counteract these effects.

Asymmetric activation of dimeric GABAB and metabotropic glutamate receptors.

G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins and are important drug targets. GPCRs are allosteric machines that transduce an extracellular signal to the cell by activating heterotrimeric G proteins. Herein, we summarize the recent advancements in the molecular activation mechanism of the γ-aminobutyric acid type B (GABAB) and metabotropic glutamate (mGlu) receptors, the most important class C GPCRs that modulate synaptic transmission in the brain. Both are mandatory dimers, this quaternary structure being needed for their function The structures of these receptors in different conformations and in complexes with G proteins have revealed their asymmetric activation. This asymmetry is further highlighted by the recent discovery of mGlu heterodimers, where the eight mGlu subunits can form specific and functional heterodimers. Finally, the development of allosteric modulators has revealed new possibilities for regulating the function of these receptors by targeting the transmembrane dimer interface. This family of receptors never ceases to astonish and serve as models to better understand the diversity and asymmetric functioning of GPCRs.NEW & NOTEWORTHY γ-aminobutyric acid type B (GABAB) and metabotropic glutamate (mGlu) receptors form constitutive dimers, which are required for their function. They serve as models to better understand the diversity and activation of G protein-coupled receptors (GPCRs). The structures of these receptors in different conformations and in complexes with G proteins have revealed their asymmetric activation. This asymmetry is further highlighted by the recent discovery of specific and functional mGlu heterodimers. Allosteric modulators can be developed to target the transmembrane interface and modulate the asymmetry.

The effect of maternal diabetes on the expression of gamma-aminobutyric acid and metabotropic glutamate receptors in male newborn rats' inferior colliculi.

Few studies have examined the molecular alterations in the auditory pathway of infants of diabetic mothers, notwithstanding the fact that maternal diabetes may have an impact on the development of the neonatal peripheral and central nervous systems. Male newborn rats were studied to determine how maternal diabetes affected the expression of gamma-aminobutyric acid (GABAAα1 and GABAB1) and metabotropic glutamate (mGlu2) receptors in the inferior colliculus (IC) in this research. Female rats were given a single intraperitoneal injection of streptozotocin (STZ) at a 65 mg/kg dose to develop a model of diabetic mothers. The study population was split into sham, diabetes without treatment, and diabetes with insulin groups. Their male neonatal rats were anesthetized on P0, P7, and P14 after mating and delivery. The receptors' distribution pattern was studied using immunohistochemistry (IHC). Pairwise comparison in the groups revealed that the GABA receptors (Aα1 and B1) were significantly downregulated in the diabetes without treatment group (p<0.001). Furthermore, pairwise comparison in the groups indicated significant mGlu2 upregulation in the diabetes without treatment group (p<0.001). Regarding the concentration of all receptors, there was no discernible distinction between the diabetes with insulin and sham groups. This investigation showed that the concentration of GABAAα1 and GABAB1 receptors decreased significantly over time, whereas the concentration of mGlu2 receptors increased significantly over time in male neonatal rats born to streptozotocin-induced diabetic mothers.

Differential Activity of Orthosteric Agonists and Allosteric Modulators at Metabotropic Glutamate Receptor 7.

Metabotropic glutamate receptor 7 (mGlu7) is a G protein coupled receptor that has demonstrated promise as a therapeutic target across a number of neurologic and psychiatric diseases. Compounds that modulate the activity of mGlu7, such as positive and negative allosteric modulators, may represent new therapeutic strategies to modulate receptor activity. The endogenous neurotransmitter associated with the mGlu receptor family, glutamate, exhibits low efficacy and potency in activating mGlu7, and surrogate agonists, such as the compound L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4), are often used for receptor activation and compound profiling. To understand the implications of the use of such agonists in the development of positive allosteric modulators (PAMs), we performed a systematic evaluation of receptor activation using a system in which mutations can be made in either protomer of the mGlu7 dimer; we employed mutations that prevent interaction with the orthosteric site as well as the G-protein coupling site of the receptor. We then measured increases in calcium levels downstream of a promiscuous G protein to assess the effects of mutations in one of the two protomers in the presence of two different agonists and three positive allosteric modulators. Our results reveal that distinct PAMs, for example N-[3-Chloro-4-[(5-chloro-2-pyridinyl)oxy]phenyl]-2-pyridinecarboxamide (VU0422288) and 3-(2,3-Difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (VU6005649), do exhibit different maximal levels of potentiation with L-AP4 versus glutamate, but there appear to be common stable receptor conformations that are shared among all of the compounds examined here. SIGNIFICANCE STATEMENT: This manuscript describes the systematic evaluation of the mGlu7 agonists glutamate and L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) in the presence and absence of three distinct potentiators examining possible mechanistic differences. These findings demonstrate that mGlu7 potentiators display subtle variances in response to glutamate versus L-AP4.

Metabotropic glutamate receptors in GtoPdb v.2023.1

Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [351]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [140]. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [200, 275, 268, 403]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organisation similar to that of other GPCRs, although the helices appear more compacted [88, 433, 62]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [217, 191] and heterodimers [91]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [89]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [270, 440, 145, 283, 259, 218]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [140]). The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [30] and antagonised by (S)-hexylhomoibotenic acid [235]. Group-II mGlu receptors may be activated by LY389795 [269], LY379268 [269], eglumegad [354, 434], DCG-IV and (2R,3R)-APDC [355], and antagonised by eGlu [170] and LY307452 [425, 105]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [130]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [185]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

VU0155041, a positive allosteric modulator of mGluR4, in the nucleus accumbens facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

Nucleus accumbens (NAc) neurons appear to be at the hub of the reward circuit. New evidence suggests that the behavioural effects of morphine substances may be significantly regulated by glutamate-mediated transmission, notably by metabotropic glutamate (mGlu) receptors. Here, we examined the hypothesis that the mGlu4 receptor within that NAc has a role in the extinction and reinstatement of morphine-induced conditioned place preference (CPP). The animals received bilaterally microinjections of VU0155041, a positive allosteric modulator (PAM) and partial agonist of mGlu4 receptor, into the NAc. In Experiment 1, the rats received VU0155041 (10, 30 and 50 μg/0.5 μL) during the extinction period. In Experiment 2, the CPP extinguished rats received VU0155041 (10, 30 and 50 μg/0.5 μL) five minutes prior to the administration of morphine (1 mg/kg) in order to reinstate the extinguished CPP. The results showed that the intra-accumbal administration of VU0155041 reduced the extinction period of CPP. Furthermore, the administration of VU0155041 into the NAc dose-dependently inhibited the reinstatement of CPP. The findings suggested that the mGluR4 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP, which could be mediated by an increase in the release of extracellular glutamate.

Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.

Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.

JNJ-42491293 is a metabotropic glutamate 2 (mGlu2) positive allosteric modulator (PAM) that was radiolabelled with [11C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10mg/kg). In the scans in which [11C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10mg/kg) to [11C]-JNJ-42491293 did not modify the SUVs obtained with [11C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human.

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine 'modulation bias' in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.

Modulation of circuit oscillations in the rat anterior cingulate cortex (ACC) in vitro by mGlu2 metabotropic glutamate receptors and alleviation of the effects of phencyclidine-induced NMDA-receptor hypofunction

Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies. The NMDA receptor blocker phencyclidine (PCP), known to evoke certain schizophrenia-like symptoms in humans, elevated the power of beta oscillations in ACC and caused a shift in oscillation frequency from the gamma range to the beta range. These enhanced beta oscillations were reduced by the Group II mGlu receptor agonists. These results show that Group II mGlu receptors, and specifically mGlu2, modulate network oscillations. Furthermore, attenuation of the effect of PCP suggests that mGlu2 receptors may stabilise aberrant network activity. These results underline the importance of Group II mGlu receptors, and particularly mGlu2, as targets for the treatment of neuropsychiatric and neurodegenerative diseases.

MGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development.

Triggered by the ground-breaking finding that ketamine exerts robust and rapid-acting antidepressant effects in patients with treatment-resistant depression, glutamatergic systems have attracted attention as targets for the development of novel antidepressants. Among glutamatergic systems, group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, are of interest because of their modulatory roles in glutamatergic transmission. Accumulating evidence has indicated that mGlu2/3 receptor antagonists have antidepressant-like effects in rodent models that mirror those of ketamine and that mGlu2/3 receptor antagonists also share underlying mechanisms with ketamine that are responsible for these antidepressant-like actions. Importantly, contrary to their antidepressant-like profile, preclinical studies have revealed that mGlu2/3 receptor antagonists are devoid of ketamine-like adverse effects, such as psychotomimetic-like behavior, abuse potential and neurotoxicity. Despite some discouraging results for an mGlu2/3 receptor antagonist decoglurant (classified as a negative allosteric modulator [NAM]) in patients with major depressive disorder, clinical trials of two mGlu2/3 receptor antagonists, a phase 2 trial of TS-161 (an orthosteric antagonist) and a phase 1 trial of DSP-3456 (a NAM), are presently on-going. mGlu2/3 receptors still hold promise for the development of safer and more efficacious antidepressants.

Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu7 Receptor Modulation Activity and Antipsychotic-Like Properties.

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.

Group I Metabotropic Glutamate Receptors Modulate Motility and Enteric Neural Activity in the Mouse Colon.

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function.

Metabotropic glutamate receptor function and regulation of sleep-wake cycles.

Metabotropic glutamate (mGlu) receptors are the most abundant family of G-protein coupled receptors and are widely expressed throughout the central nervous system (CNS). Alterations in glutamate homeostasis, including dysregulations in mGlu receptor function, have been indicated as key contributors to multiple CNS disorders. Fluctuations in mGlu receptor expression and function also occur across diurnal sleep-wake cycles. Sleep disturbances including insomnia are frequently comorbid with neuropsychiatric, neurodevelopmental, and neurodegenerative conditions. These often precede behavioral symptoms and/or correlate with symptom severity and relapse. Chronic sleep disturbances may also be a consequence of primary symptom progression and can exacerbate neurodegeneration in disorders including Alzheimer's disease (AD). Thus, there is a bidirectional relationship between sleep disturbances and CNS disorders; disrupted sleep may serve as both a cause and a consequence of the disorder. Importantly, comorbid sleep disturbances are rarely a direct target of primary pharmacological treatments for neuropsychiatric disorders even though improving sleep can positively impact other symptom clusters. This chapter details known roles of mGlu receptor subtypes in both sleep-wake regulation and CNS disorders focusing on schizophrenia, major depressive disorder, post-traumatic stress disorder, AD, and substance use disorder (cocaine and opioid). In this chapter, preclinical electrophysiological, genetic, and pharmacological studies are described, and, when possible, human genetic, imaging, and post-mortem studies are also discussed. In addition to reviewing the important relationships between sleep, mGlu receptors, and CNS disorders, this chapter highlights the development of selective mGlu receptor ligands that hold promise for improving both primary symptoms and sleep disturbances.

Metabotropic glutamate receptors and cognition: From underlying plasticity and neuroprotection to cognitive disorders and therapeutic targets.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors that play pivotal roles in mediating the activity of neurons and other cell types within the brain, communication between cell types, synaptic plasticity, and gene expression. As such, these receptors play an important role in a number of cognitive processes. In this chapter, we discuss the role of mGlu receptors in various forms of cognition and their underlying physiology, with an emphasis on cognitive dysfunction. Specifically, we highlight evidence that links mGlu physiology to cognitive dysfunction across brain disorders including Parkinson's disease, Alzheimer's disease, Fragile X syndrome, post-traumatic stress disorder, and schizophrenia. We also provide recent evidence demonstrating that mGlu receptors may elicit neuroprotective effects in particular disease states. Lastly, we discuss how mGlu receptors can be targeted utilizing positive and negative allosteric modulators as well as subtype specific agonists and antagonist to restore cognitive function across these disorders.

MGlu3 Metabotropic Glutamate Receptors as a Target for the Treatment of Absence Epilepsy: Preclinical and Human Genetics Data.

Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for treating absence epilepsy. However, no information is available on mGlu3 receptors. To examine whether (i) changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spikewave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; realtime PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.

Contribution of the Roman rat lines/strains to personality neuroscience: neurobehavioral modeling of internalizing/externalizing psychopathologies.

The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and increased sensitivity to frustration. Thus, RLA rats' phenotypic profile falls well within the "internalizing" behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant sensitization and drug addiction. Thus, RHA rats' phenotypes are consistent with a "disinhibiting externalizing" profile. Many neurobiological/molecular traits differentiate both rat lines/strains. For example, relative to RLA rats, RHAs exhibit decreased function of the prefrontal cortex (PFC), hippocampus and amygdala, increased functional tone of the mesolimbic dopamine system, a deficit of central metabotropic glutamate-2 (mGlu2) receptors, increased density of serotonin 5-HT2A receptors in the PFC, impairment of GABAergic transmission in the PFC, alterations of several synaptic markers and increased density of pyramidal immature dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. We review evidence supporting RLA rats as a valid model of anxiety/fear, stress and frustration vulnerability, whereas RHA rats represent a promising translational model of neurodevelopmental alterations related to impulsivity, schizophrenia-relevant features and comorbidity with drug addiction vulnerability.