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

NEUROPHARMACOLOGY

卷:178

Article

Celli, Roberta¹  Wall, Mark J.²  Santolini, Ines¹  Vergassola, Matteo³  Di Menna, Luisa¹  Mascio, Giada¹  Cannella, Milena¹  van Luijtelaar, Gilles⁴  Pittaluga, Anna³  Ciruela, Francisco^5,6  Bruno, Valeria^1,7  Nicoletti, Ferdinando^1,7  Ngomba, Richard T.⁸ 

[1] RCCS Neuromed, Pozzilli, Italy

[2] Univ Warwick, Sch Life Sci, Coventry, W Midlands, England

[3] Univ Genoa, Dept Pharm, Genoa, Italy

[4] Radboud Univ Nijmegen, Donders Ctr Cognit, Nijmegen, Netherlands

[5] Univ Barcelona, Fac Med & Ciencies Salut, Dept Patol & Terapeut Expt, IDIBELL, Barcelona, Spain

[6] Univ Barcelona, Inst Neurociencies, Barcelona, Spain

[7] Univ Sapienza, Dept Physiol, Rome, Italy

[8] Univ Lincoln, Sch Pharm, Lincoln, England

关键词: mGlu5 receptors;    Ventrobasal thalamus;    Somatosensory cortex;    GABA uptake;    GAT-1;    Tonic inhibition;   

DOI  :  10.1016/j.neuropharm.2020.108240

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free