A growing body of evidence suggests that mGlu5 receptors are candidate targets for the treatment of absence epilepsy. Pharmacological treatment with the mGlu5 receptor positive allosteric modulator (PAM), VU0360172, reduced spike-and-wave discharges (SWDs) in the WAG/Rij rats, which develop absence seizures after 2-3 months of age. However, intrathalamic injection of VU0360172 enhanced the incidence of SWDs when co-injected with tiagabine, a GABA transporter (GAT-1) inhibitor. This inversed synergism suggested that modulation of GAT-1 was essential for the anti-absence activity of mGlu5 receptors.
We measured GAT-1 expression in the thalamus and somatosensory cortex of pre-symptomatic and symptomatic WAG/Rij rats and age-matched controls, in which only thalamic levels of GAT-1 increased one hour after a single s.c. injection of VU0360172.
GABA uptake was measured in symptomatic WAG/Rij rats after acute or repeated injections of VU0360172, in synaptosomal preparations from the thalamus and somatosensory cortex incubated with [3H]GABA. Both single and repeated injections of VU0360172 significantly enhanced [3H]GABA uptake in thalamic synaptosomes, whereas in cortical synaptosomes the acute treatment with VU0360172 reduced GABA uptake. These findings strongly suggest that mGlu5 receptors negatively modulate GABAergic transmission in the cortico-thalamo-cortical network by up-regulating GAT-1, and support the development of mGlu5 PAMs as potential anti-absence drugs. We are now exploring the molecular mechanism underlying the fast up-regulation of GAT-1 and the ensuing GABA uptake in the thalamus in response to mGlu5 receptor activation using primary cultures of thalamic astrocytes incubated with selective inhibitors of enzymes directly involved in mGlu5 receptor signaling. In addition, electrophysiological experiments will examine whether activation of mGlu5 receptors influences tonic GABAergic inhibition.
Optimization of drug treatment of absence epilepsy is an important medical need. The expected findings will pave the way to the clinical development of mGlu5 receptor PAMs for the treatment of absence epilepsy. The project is highly innovative because there are no drugs targeting mGlu receptors in the treatment of absence epilepsy and epilepsy in general. Data obtained with mGlu5 receptor PAMs in animal models of psychosis and cognitive dysfunction have consistently shown that these drugs do not cause the typical adverse effects of antiepileptic drugs, such as sedation, ataxia, dizziness and diplopia. Thus, innovation is inherent to the development of a new class of agents that (presumably) modulate thalamic GABAergic neurotransmission acting primarily on mGlu5 receptors, and endowed with a good profile of
safety and tolerability.