Modulation Of mGlu5 Receptors Research Articles

Effects of the Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5, VU-29, on Impairment of Novel Object Recognition Induced by Acute Ethanol and Ethanol Withdrawal in Rats

Glutamate is essential for learning and memory processes, and acute and chronic exposures to ethanol (or protracted abstinence) alter glutamatergic transmission. In the current study, we investigated the effects of VU-29, positive allosteric modulator of metabotropic glutamate 5 (mGlu5) receptor, on the acute ethanol- and ethanol withdrawal-induced impairment of novel object recognition (NOR) task in rats. The influence of VU-29 (30 mg/kg) on memory retrieval was measured (a) at 4-h delay after acute ethanol administration, as well as (b) after acute withdrawal (24 and 48 h) of repeated (2.0 g/kg, once daily for 7 days) ethanol administration. Additionally, the effects of VU-29 on expression of mGlu5 and mGlu2 receptor proteins in the hippocampus, prefrontal cortex, and striatum were determined 48 h after ethanol withdrawal. Our results indicated that VU-29, given before acute ethanol administration, prevented the ethanol-induced impairments in spatial memory retrieval. Furthermore, VU-29 given before the testing session on the first day of abstinence facilitated NOR performance in ethanol-withdrawn rats at 4- and 24-h delay after administration. Our ELISA results show that VU-29 normalized ethanol withdrawal induced increase in expression of mGlu5 receptor protein in the hippocampus, prefrontal cortex, and striatum, as well as expression of mGlu2 receptor protein in the hippocampus. Thus, results from our study indicate that positive modulation of mGlu5 receptor prevented and reversed ethanol-induced memory impairment. Moreover, mGlu5 (hippocampus, prefrontal cortex, and striatum) and mGlu2 (hippocampus) receptors play an important role in the ethanol-induced recognition memory impairment induced by ethanol withdrawal.

Allosteric modulation of mGlu5 receptors by MPEP protects against hepatic cold ischemia and reperfusion injury

Allosteric modulation of mGlu5 receptors by MPEP protects against hepatic cold ischemia and reperfusion injury

Modulatory effect of mGlu5 receptor antagonism on corticostriatal synaptic plasticity in a DYT1 knockin mouse model of dystonia

Event Abstract Back to Event Modulatory effect of mGlu5 receptor antagonism on corticostriatal synaptic plasticity in a DYT1 knockin mouse model of dystonia MARTA MALTESE1*, GIULIA PONTERIO2, Giuseppina Martella1, SONIA POLI3 and Antonio Pisani1 1 University of Rome "Tor Vergata", Italy 2 SANTA LUCIA FOUNDATION, Italy 3 ADDEX THERAPEUTICS, Switzerland Early onset torsion dystonia (DYT1) is an autosomal dominant disorder caused by a 3-bp deletion in TOR1A gene encoding for protein torsinA. Evidence suggested that TOR1A mutation induces an aberrant neuronal signalling within the striatum. Indeed, our findings on different mouse models of DYT1 dystonia demonstrated that striatal cholinergic interneurons (ChIs) activity and corticostriatal synaptic plasticity are profoundly affected. Recently, we have demonstrated that the negative allosteric modulator (NAM) of mGlu5 receptor (ADX48621, dipraglurant) counteracts the excitatory response of D2 dopamine receptor in ChIs from knockin mice heterozygous for Δ-torsinA (Tor1a+/Δgag mice). Corticostriatal synaptic plasticity could be modulated by metabotropic glutamate receptor group I (mGlu1 and 5), particularly mGlu5. Here, by means of electrophysiological recording we evaluated the effect of ADX48621 on short- and long-term synaptic plasticity in striatal medium spiny neurons (MSNs) from Tor1a+/Δgag mice compared to wild-type littermates (Tor1a +/+ mice). As previously reported, Tor1a+/Δgag mice exhibited a significant impairment of corticostriatal bidirectional synaptic plasticity in particular long term depression (LTD) was lost. To evaluate the potential role of mGlu5 receptor modulation on the altered synaptic plasticity we performed a chronic treatment with dipraglurant in adult mice (intraperitoneal injection, 50mg/kg, 8 days). This procedure was able to partially restore a physiological LTD as well as a physiological synaptic depotentiation (SD) in MSNs from Tor1a +/Δgag mice. Conversely in wild type mice ADX48621 did not significantly affect the synaptic plasticity of MSNs. In both Tor1a +/+ and Tor1a +/Δgag mice ADX48621 did not change both intrinsic membrane properties of MSNs and paired pulse ratio (PPR). Our results suggest that modulation of mGlu5 receptor could represent a novel potential target in treatment of DYT1 dystonia. Figure 1 Keywords: Dystonia, dipraglurant, mGlu5, LTD, Striatum Conference: 5th Biennial Workshop on Dystonia: “Controversies in Dystonia and Parkinsonism” | Nobile Collegio Chimico Farmaceutico, Rome, May 29-30, 2015, Rome, Italy, 29 May - 30 May, 2015. Presentation Type: Poster presentation Topic: Dystonia Citation: MALTESE M, PONTERIO G, Martella G, POLI S and Pisani A (2015). Modulatory effect of mGlu5 receptor antagonism on corticostriatal synaptic plasticity in a DYT1 knockin mouse model of dystonia. Front. Neurol. Conference Abstract: 5th Biennial Workshop on Dystonia: “Controversies in Dystonia and Parkinsonism” | Nobile Collegio Chimico Farmaceutico, Rome, May 29-30, 2015. doi: 10.3389/conf.fneur.2015.57.00001 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Apr 2015; Published Online: 23 Apr 2015. * Correspondence: Dr. MARTA MALTESE, University of Rome "Tor Vergata", Rome, Italy, maltese@med.uniroma2.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers MARTA MALTESE GIULIA PONTERIO Giuseppina Martella SONIA POLI Antonio Pisani Google MARTA MALTESE GIULIA PONTERIO Giuseppina Martella SONIA POLI Antonio Pisani Google Scholar MARTA MALTESE GIULIA PONTERIO Giuseppina Martella SONIA POLI Antonio Pisani PubMed MARTA MALTESE GIULIA PONTERIO Giuseppina Martella SONIA POLI Antonio Pisani Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Synaptic Plasticity as a Therapeutic Target in the Treatment of Autism-related Single-gene Disorders

The term "Autism Spectrum" is often used to describe disorders that are currently classified as Pervasive Developmental Disorders. These disorders are typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviors and/or cognitive delays or mental retardation; sometimes they present high comorbidity rates with epilepsy. Although these diagnoses share some common features, individuals with these disorders are thought to be "on the spectrum" because of differences in severity across these domains. Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. Of particular interest are transgenic technologies that allowed the engineering of several mouse models mimicking different kinds of monogenic heritable forms of ASDs. These transgenic models provide excellent opportunities to explore in detail cellular and molecular mechanisms underlying disease pathology and to identify novel targets for therapeutic intervention. Increasing evidence suggests that the pathophysiological core of the murine model is primarily due to changes in normal synaptic transmission and plasticity. Here, we will extensively review the synaptic alterations across different animal models of ASDs and recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. We describe how pharmacological modulation of mGlu5 receptor, through the use of positive or negative allosteric modulators (depending on the specific disorder), may represent a promising therapeutic strategy for ASDs treatment.

Up-regulation of astrocyte metabotropic glutamate receptor 5 by amyloid-β peptide

The effects of amyloid-beta peptide (Aβ) on astrocyte responses to activation of mGlu5 receptors have been investigated using calcium imaging. Pre-incubation with Aβ1–40 peptide for up to 72 h produced a time- and concentration-dependent 2–4 fold enhancement in the magnitude of the intracellular calcium mobilization response to the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). In contrast, pre-treatment with Aβ1–40 did not alter the calcium responses induced by other G protein coupled- or ion channel-receptors. Aβ 1–40-enhanced DHPG responses were blocked by the mGlu5 antagonist MPEP but not by inhibitors of voltage dependent calcium channels or by the AMPA/KA receptor antagonist CNQX. Up-regulation of mGlu5 coupled responses was associated with significant increases in astrocyte mGlu5 receptor- mRNA and -protein expression after preincubation with Aβ . The changes observed in vitro were consistent with results obtained from human Alzheimer's disease (AD) patients. Immunostaining for mGlu5 receptors was increased on astrocytes which were colocalized with Aβ plaques in hippocampal tissue from AD patients compared to age-matched controls. These results suggest that modulation of mGlu5 receptors in astrocytes could be an important mechanism in determining the progression of pathology in AD.

Bursting of Prefrontal Cortex Neurons in Awake Rats is Regulated by Metabotropic Glutamate 5 (mGlu5) Receptors: Rate-dependent Influence and Interaction with NMDA Receptors

Metabotropic glutamate 5 (mGlu5) receptors have been recently implicated in prefrontal cortex (PFC)-dependent executive functions because inhibition of mGlu5 receptors impairs working memory and worsens cognitive-impairing effects of NMDA receptor antagonists. To better understand the mechanisms by which mGlu5 receptors influence PFC function, we examined the effects of selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), given alone or in combination with the NMDA receptor antagonist MK801, on ensemble single unit activity in the medial PFC (mPFC) of behaving rats. MPEP decreased the spontaneous burst activity of the majority of mPFC neurons. This inhibition was selective for the most active cells because greater decreases were observed in neurons with higher baseline firing rates. MPEP augmented the effects of MK801 on burst activity, variability of spike firing and random spike activity. These findings demonstrate that in awake animals mGlu5 receptors regulate the function of PFC neurons by two related mechanisms: (i) rate-dependent excitatory influence on spontaneous burst activity; and (ii) potentiation of NMDA receptor mediated effects on firing rate and burst activity. These mechanisms support the idea that modulation of mGlu5 receptors may provide a pharmacological strategy for fine-tuning the temporal pattern of firing of PFC neurons.