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Activation of mGlu 3 disrupts reconsolidation of contextual fear memory. (a) Schematic of the behavioral testing protocol. (b) Propranolol and LY379268 disrupt reconsolidation of contextual fear memory as demonstrated by decreased freezing during 5 min context exposure. The mGlu 3 NAM VU0650786 reverses the disruption induced by LY379268. (c) The A 1 receptor agonist CCPA dose-dependently disrupts reconsolidation. (d and e) The A 1 antagonist PQ69 had no effect alone, but blocks the disruption induced by LY379268. (f) A model for mGlu 3-mediated glialneuronal communication at the SC-CA1 hippocampal synapse. When glial mGlu 3 is coincidently activated with β-adrenergic receptors (βARs), the βAR-mediated production of cAMP by stimulation of adenylate cyclase (AC) is greatly potentiated. cAMP metabolites then activate A 1 adenosine receptors presynaptically expressed on the Schaffer Collateral (SC) terminals, resulting in a depression of neurotransmission at the SC-CA1 synapse in the hippocampus. This glial-neuronal signaling also results in antagonism of βAR agonist-mediated potentiation of weak TBS-induced LTP. Quantification of contextual fear memory on testing day presented as mean ± SEM of the percentage of time freezing during the 5-min context exposure. Inset numbers in bars indicate the number of animals in each condition. *p ⩽ 0.05 and **po0.01 relative to vehicle-treated animals.
Source publication
Activation of β-adrenergic receptors (βARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with βARs in the hippocampal astrocytes induces...
Contexts in source publication
Context 1
... we reasoned that activation of mGlu 3 could inhibit forms of hippocampal-dependent learning that are dependent on βAR activation in a manner similar to βAR antagonists. To test this hypothesis, we trained rats in a contextual fear memory reconsolidation task (Figure 5a). As previously reported (Taherian et al, 2014), propranolol-treated animals exhibited significantly less freezing (Figure 5b; 29.6 ± 4.6%) vs vehicle-treated rats (56.1 ± 8.3%; F (5,73) = 3347, po0.05, ...
Context 2
... test this hypothesis, we trained rats in a contextual fear memory reconsolidation task (Figure 5a). As previously reported (Taherian et al, 2014), propranolol-treated animals exhibited significantly less freezing (Figure 5b; 29.6 ± 4.6%) vs vehicle-treated rats (56.1 ± 8.3%; F (5,73) = 3347, po0.05, Dunnett's post-test vs vehicle po0.05), indicative of a disruption of memory reconsolidation. ...
Context 3
... we tested the hypothesis that A 1 receptor activation could disrupt reconsolidation. Similar to the effects we observed with propranolol and LY379268, the selective A 1 agonist CCPA dose-dependently (0.1-0.15 mg/kg) decreased freezing dur- ing the context test (Figure 5c) reaching significance at the highest dose tested (26.8 ± 5.8%; F (2,31) = 3.351, po0.05; Dunnett's post-test po0.05 vs vehicle). ...
Context 4
... of PQ69 (0.3-1 mg/kg) on freezing during the context test (Figure 5d; F (2,31) = 1.720 p40.05). However, when co-administered with LY37268 (3 mg/kg), PQ69 (1 mg/kg) blocked the disruption effects of LY37268 in reducing freezing behavior vs vehicle (Figure 5e; F (2,35) = 6.024, po0.05; ...
Context 5
... of PQ69 (0.3-1 mg/kg) on freezing during the context test (Figure 5d; F (2,31) = 1.720 p40.05). However, when co-administered with LY37268 (3 mg/kg), PQ69 (1 mg/kg) blocked the disruption effects of LY37268 in reducing freezing behavior vs vehicle (Figure 5e; F (2,35) = 6.024, po0.05; Dunnett's post-test vs vehicle p40.05). ...
Context 6
... conclusion, the results of the present studies provide a conceptual framework in which mGlu 3 and βARs interact to influence cAMP signaling, synaptic plasticity, and potential behavior (Figure 5f). Noradrenergic afferents can modulate cellular excitability and potentiate LTP through neuronal βARs. ...
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Metabotropic glutamate receptors (mGluRs) play an important role in synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic...
Metabotropic glutamate receptors (mGluRs) play an important role in synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic...
Metabotropic glutamate receptors (mGluRs) play an important role in synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic...
Citations
... This has an inhibitory effect on neurons, whereby downregulation of cAMP and PKA mediate membrane hyperpolarization by increasing the open probability of G-protein inward rectifier K + channels (Armbruster et al., 2007;Witkowski et al., 2012;. However, Gi-GPCR stimulation in astrocytes can elicit Ca 2+ elevations, a marker of cellular activation, alongside reduced (Sobolczyk and Boczek, 2022) or elevated cAMP levels (Tang and Gilman, 1991;Walker et al., 2017). Conversely, Gs-GPCRs upregulate cAMP production and are therefore regarded as stimulatory in neurons -however are generally reported to not mediate Ca 2+ elevations in astrocytes (Shigetomi et al., 2019;Oe et al., 2020). ...
... βAR activation is also known to mediate cAMP accumulation (Catus et al., 2011;Vardjan et al., 2014) leading to increased process branching in primary rat cultures (Vardjan et al., 2014), indicating a role for βARs in morphological plasticity. Astrocytic βAR activity in the mouse hippocampus is also shown to enhance LTP (Walker et al., 2017). In the rat hippocampus, astrocytic βAR antagonism prior to learning had no effect on shortterm memory but significantly impaired recent and remote longterm memory, indicating activation of astrocytic βARs promotes memory consolidation (Gao et al., 2016). ...
... However, GABAbR activation is known to be negatively coupled to cAMP in rat primary astrocyte cultures (Patte et al., 1999). It has also been shown for hippocampal astrocytes that, quite counterintuitively, mGluR3 activity can potentiate cAMP elevations elicited by Gscoupled βARs via Gi-βγ subunits as illustrated in Figure 1 (Tang and Gilman, 1991;Walker et al., 2017). Interestingly, mGluR3 potentiation of βAR-induced cAMP elevations disrupts βAR-mediated LTP induction and contextual fear learning, to a similar degree as direct βAR antagonism. ...
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have proven themselves as one of the key in vivo techniques of modern neuroscience, allowing for unprecedented access to cellular manipulations in living animals. With respect to astrocyte research, DREADDs have become a popular method to examine the functional aspects of astrocyte activity, particularly G-protein coupled receptor (GPCR)-mediated intracellular calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) dynamics. With this method it has become possible to directly link the physiological aspects of astrocytic function to cognitive processes such as memory. As a result, a multitude of studies have explored the impact of DREADD activation in astrocytes on synaptic activity and memory. However, the emergence of varying results prompts us to reconsider the degree to which DREADDs expressed in astrocytes accurately mimic endogenous GPCR activity. Here we compare the major downstream signaling mechanisms, synaptic, and behavioral effects of stimulating Gq-, Gs-, and Gi-DREADDs in hippocampal astrocytes of adult mice to those of endogenously expressed GPCRs.
... The presynaptic mGluR-2,3 (group II) are prominently expressed in limbic brain regions and are crucial for the regulation of the excessive glutamate release [148]. Activation of mGluR group II by orthosteric agonists has been shown to enhance the function of NMDA-Rs [149] and regulate the long-term potentiation and depression in the prefrontal cortex and the hippocampus [150,151]. Following positive preclinical studies with mGluR-2 PAMs [152], the first promising substance from this category that reached clinical trials was pomaglumetad methionil (LY2140023 monohydrate, a prodrug of the mGluR-2/3 agonist, LY404039), developed by Eli Lilly and Company. ...
Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D2/D3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies.
... Early studies in rodents with the mGluR2/3 agonist LY354740 revealed an improvement in deficits in stereotypy, locomotion, spatial working memory, and cortical glutamate efflux caused by the NMDAR antagonist PCP (Moghaddam and Adams, 1998). Activation of mGluR2/3 receptors has since been shown to enhance NMDAR function (Tyszkiewicz et al., 2004), regulate long-term depression and long-term potentiation in the PFC and hippocampus, respectively (Walker et al., 2017;Walker et al., 2015), and reduces excessive activity at glutamatergic synapses in the PFC (Homayoun et al., 2005). Inhumans, these findings were supported by the demonstration that mGluR2/3 agonist administration can attenuate the disruptions in working memory that are produced by the NMDAR antagonist ketamine (Krystal et al., 2005). ...
Research into the neurobiological processes that may lead to the onset of schizophrenia places growing emphasis on the glutamatergic system and brain development. Preclinical studies have shown that neurodevelopmental, genetic, and environmental factors contribute to glutamatergic dysfunction and schizophrenia-related phenotypes. Clinical research has suggested that altered brain glutamate levels may be present before the onset of psychosis and relate to outcome in those at clinical high risk. After psychosis onset, glutamate dysfunction may also relate to the degree of antipsychotic response and clinical outcome. These findings support ongoing efforts to develop pharmacological interventions that target the glutamate system and could suggest that glutamatergic compounds may be more effective in specific patient subgroups or illness stages. In this review, we consider the updated glutamate hypothesis of schizophrenia, from a neurodevelopmental perspective, by reviewing recent preclinical and clinical evidence, and discuss the potential implications for novel therapeutics.
... Neurochemicals can influence the intrinsic properties described above and in Fig. 1 via a range of metabotropic receptors including metabotropic glutamate receptors (mGluRs) (Walker et al., 2017), metabotropic GABA receptors (e.g. GABA B receptors) (Ault and Nadler, 1982), muscarinic acetylcholine receptors (Hasselmo, 2006), most of the serotonin receptor subtypes (Matias et al., 2017;Lottem et al., 2018) and all receptors to dopamine (Durstewitz and Seamans, 2002) and norepinephrine (Usher et al., 1999). ...
The space of possible neural models is enormous and under-explored. Single cell computational neuroscience models account for a range of dynamical properties of membrane potential, but typically do not address network function. In contrast, most models focused on network function address the dimensions of excitatory weight matrices and firing thresholds without addressing the complexities of metabotropic receptor effects on intrinsic properties. There are many under-explored dimensions of neural parameter space, and the field needs a framework for representing what has been explored and what has not. Possible frameworks include maps of parameter spaces, or efforts to categorize the fundamental elements and molecules of neural circuit function. Here we review dimensions that are under-explored in network models that include the metabotropic modulation of synaptic plasticity and presynaptic inhibition, spike frequency adaptation due to calcium-dependent potassium currents, and afterdepolarization due to calcium-sensitive non-specific cation currents and hyperpolarization activated cation currents. Neuroscience research should more effectively explore possible functional models incorporating under-explored dimensions of neural function.
... The effects of propranolol on disruption of memory reconsolidation seem to depend on activation of metabotropic glutamate class II receptor 153 . This is of interest, because both alcohol-dependent patients and rats show deficits in mGluR2 receptors within the mPFC 80 , which would predict increased stability of memories and in turn reduced cognitive flexibility. ...
Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for ~5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with “alcohol dependence” or simply “alcoholism”), a condition characterized by a systematically biased choice preference for alcohol at the expense of healthy rewards, and continued use despite adverse consequences (“compulsivity”). Alcoholism is arguably the most pressing area of unmet medical needs in psychiatry, with only a small fraction of patients receiving effective, evidence-based treatments. Medications currently approved for the treatment of alcoholism have small effect sizes, and their clinical uptake is negligible. No mechanistically new medications have been approved since 2004, and promising preclinical results have failed to translate into novel treatments. This has contributed to a reemerging debate whether and to what extent alcohol addiction represents a medical condition, or reflects maladaptive choices without an underlying brain pathology. Here, we review this landscape, and discuss the challenges, lessons learned, and opportunities to retool drug development in this important therapeutic area.
... Overall, these findings add support to the hypothesis that mGlu2, and not mGlu3, mediates the effects of orthosteric mGlu2/3 receptor agonists preventing psychosis-like behaviors. Nevertheless, considering recent findings suggesting that activation of the mGlu3 receptor in the frontal cortex leads to cognitive improvement in rodent models [50,51], further work will be needed to test whether One-way ANOVA with Bonferroni's post hoc test (n.s., not significant; *P < 0.05, **P < 0.01, ***P < 0.001) mGlu3 receptor is involved in the effects of LY379268 in rodent models of alterations in cognitive and sensorimotor gating processes induced by dissociative agents. The serotonergic profile of atypical antipsychotics is suggested to contribute to their therapeutic advantage of atypical antipsychotics over typical dopaminergic antipsychotics [43,52]. ...
Following the publication of this article Figs. 3b, c were published incorrectly. Also in sub-panel c of Fig. 4, ‘Chronic cloza ine’ should read ‘Chronic clozapine’.
... Overall, these findings add support to the hypothesis that mGlu2, and not mGlu3, mediates the effects of orthosteric mGlu2/3 receptor agonists preventing psychosis-like behaviors. Nevertheless, considering recent findings suggesting that activation of the mGlu3 receptor in the frontal cortex leads to cognitive improvement in rodent models [50,51], further work will be needed to test whether mGlu3 receptor is involved in the effects of LY379268 in rodent models of alterations in cognitive and sensorimotor gating processes induced by dissociative agents. The serotonergic profile of atypical antipsychotics is suggested to contribute to their therapeutic advantage of atypical antipsychotics over typical dopaminergic antipsychotics [43,52]. ...
Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication restricted the therapeutic effects of these glutamatergic agents. However, little is known about the molecular mechanism underlying the potential repercussion of previous antipsychotic exposure on the therapeutic performance of mGlu2/3 receptor agonists. Here we show that this maladaptive effect of antipsychotic treatment is mediated mostly via histone deacetylase 2 (HDAC2). Chronic treatment with the antipsychotic clozapine led to a decrease in mouse frontal cortex mGlu2 mRNA, an effect that required expression of both HDAC2 and the serotonin 5-HT2A receptor. This transcriptional alteration occurred in association with HDAC2-dependent repressive histone modifications at the mGlu2 promoter. We found that chronic clozapine treatment decreased via HDAC2 the capabilities of the mGlu2/3 receptor agonist LY379268 to activate G-proteins in the frontal cortex of mice. Chronic clozapine treatment blunted the antipsychotic-related behavioral effects of LY379268, an effect that was not observed in HDAC2 knockout mice. More importantly, co-administration of the class I and II HDAC inhibitor SAHA (vorinostat) preserved the antipsychotic profile of LY379268 and frontal cortex mGlu2/3 receptor density in wild-type mice. These findings raise concerns on the design of previous clinical studies with mGlu2/3 agonists, providing the rationale for the development of HDAC2 inhibitors as a new epigenetic-based approach to improve the currently limited response to treatment with glutamatergic antipsychotics.
Objectives:
Recent evidence indicates that hippocampus is important for conditioned fear memory (CFM). Though few studies consider the roles of various cell types' contribution to such a process, as well as the accompanying transcriptome changes during this process. The purpose of this study was to explore the transcriptional regulatory genes and the targeted cells that are altered by CFM reconsolidation.
Methods:
A fear conditioning experiment was established on adult male C57 mice, after day 3 tone-cued CFM reconsolidation test, hippocampus cells were dissociated. Using single cell RNA sequencing (scRNA-seq) technique, alterations of transcriptional genes expression were detected and cell cluster analysis were performed and compared with those in sham group.
Results:
Seven non-neuronal and eight neuronal cell clusters (including four known neurons and four newly identified neuronal subtypes) has been explored. Among them, CA subtype 1 has characteristic gene markers of Ttr and Ptgds, which is speculated to be the outcome of acute stress and promotes the production of CFM. The results of KEGG pathway enrichment indicate the differences in the expression of certain molecular protein functional subunits in long-term potentiation (LTP) pathway between two types of neurons (DG and CA1) and astrocytes, thus providing a new transcriptional perspective for the role of hippocampus in the CFM reconsolidation. More importantly, the correlation between the reconsolidation of CFM and neurodegenerative diseases-linked genes is substantiated by the results from cell-cell interactions and KEGG pathway enrichment. Further analysis shows that the reconsolidation of CFM inhibits the risk-factor genes App and ApoE in Alzheimer's Disease (AD) and activates the protective gene Lrp1.
Conclusions:
This study reports the transcriptional genes expression changes of hippocampal cells driven by CFM, which confirm the involvement of LTP pathway and suggest the possibility of CFM-like behavior in preventing AD. However, the current research is limited to normal C57 mice, and further studies on AD model mice are needed to prove this preliminary conclusion.
Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu3 receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu3 receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu3 receptor negative allosteric modulators (NAMs) induce rapid antidepressant-like effects in both acute and chronic stress models. Activation of mGlu3 receptors can enhance cognition in the rodents modeling schizophrenia-like pathophysiology. The mGlu3 receptors expressed in the astrocytes induce neuroprotective effects. Although polymorphisms in GRM3 have been shown to be associated with addiction, there is not significant evidence about the efficacy of mGlu3 receptor ligands in rodent models of addiction. Collectively, drugs targeting mGlu3 receptors may provide an alternative approach to fill the unmet clinical need for safer and more efficacious therapeutics for CNS disorders.
Metabotropic glutamate (mGlu) receptors are promising targets for the treatment of affective disorders and alcohol use disorder (AUD). Nonspecific ligands for Group II (mGlu2 and mGlu3) mGlu receptors have demonstrated consistent therapeutic potential for affective disorders in preclinical models. Disentangling the specific roles of mGlu2 versus mGlu3 receptors in these effects has persisted as a major challenge, in part due to pharmacological limitations. However, the recent development of highly specific allosteric modulators for both mGlu2 and mGlu3 receptors have enabled straightforward and rigorous investigations into the specific function of each receptor. Here, we review recent experiments using these compounds that have demonstrated both similar and distinct receptor functions in behavioral, molecular, and electrophysiological measures associated with basal function and preclinical models of affective disorders. Studies using these selective drugs have demonstrated that mGlu2 is the predominant receptor subclass involved in presynaptic neurotransmitter release in prefrontal cortex. By contrast, the activation of postsynaptic mGlu3 receptors induces a cascade of cellular changes that results in AMPA receptor internalization, producing long-term depression and diminishing excitatory drive. Acute stress decreases the mGlu3 receptor function and dynamically alters transcript expression for both mGlu2 (Grm2) and mGlu3 (Grm3) receptors in brain areas involved in reward and stress. Accordingly, both mGlu2 and mGlu3 negative allosteric modulators show acute antidepressant-like effects and potential prophylactic effects against acute and traumatic stressors. The wide array of effects displayed by these new allosteric modulators of mGlu2 and mGlu3 receptors suggest that these drugs may act through improving endophenotypes of symptoms observed across several neuropsychiatric disorders. Therefore, recently developed allosteric modulators selective for mGlu2 or mGlu3 receptors show promise as potential therapeutics for affective disorders and AUD.
