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Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission

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Celli, Roberta, Wall, Mark J., Santolini, Ines, Vergassola, Matteo, Di Menna, Luisa, Mascio, Giada, Cannella, Milena, van Luijtelaar, Gilles, Pittaluga, Anna, Ciruela, Francisco, Bruno, Valeria, Nicoletti, Ferdinando and Ngomba, Richard T. (2020) Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission. Neuropharmacology, 178 . 108240. doi:10.1016/j.neuropharm.2020.108240

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Official URL: https://doi.org/10.1016/j.neuropharm.2020.108240

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Abstract

Previous studies have shown that injection of the mGlu5 receptor positive allosteric modulator (PAM) VU0360172 into either the thalamus or somatosensory cortex markedly reduces the frequency of spike-and-wave discharges (SWDs) in the WAG/Rij model of absence epilepsy. Here we have investigated the effects of VU0360172 on GABA transport in the thalamus and somatosensory cortex, as possible modes of action underlying the suppression of SWDs. Systemic VU0360172 injections increase GABA uptake in thalamic synaptosomes from epileptic WAG/Rij rats. Consistent with this observation, VU0360172 could also enhance thalamic GAT-1 protein expression, depending on the dosing regimen. This increase in GAT-1 expression was also observed in the thalamus from non-epileptic rats (presymptomatic WAG/Rij and Wistar) and appeared to occur selectively in neurons. The tonic GABAA receptor current present in ventrobasal thalamocortical neurons was significantly reduced by VU0360172 consistent with changes in GAT-1 and GABA uptake. The in vivo effects of VU0360172 (reduction in tonic GABA current and increase in GAT-1 expression) could be reproduced in vitro by treating thalamic slices with VU0360172 for at least 1 h and appeared to be dependent on the activation of PLC. Thus, the effects of VU0360172 do not require an intact thalamocortical circuit. In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Neurosciences, Epilepsy, Sensorimotor cortex, GABA -- Receptors, Neural transmission -- Regulation
Journal or Publication Title: Neuropharmacology
Publisher: Elsevier
ISSN: 0028-3908
Official Date: 1 November 2020
Dates:
DateEvent
1 November 2020Published
6 August 2020Available
11 July 2020Accepted
Date of first compliant deposit: 10 October 2020
Volume: 178
Article Number: 108240
DOI: 10.1016/j.neuropharm.2020.108240
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
PGE1702Epilepsy Research UKhttp://dx.doi.org/10.13039/501100000295

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