Ricerc@Sapienza

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.