Rationale: 

Glutamate, the most abundant excitatory neurotransmitter in the central nervous system, is well known to be implicated in epileptic seizures. Vesicular glutamate transporters (vGLUTs) are responsible for loading synaptic vesicles with glutamate. There are 3 vGLUT isoforms molecularly identified in the mammalian brain: vGLUT1-3. Recent published data show up-regulated expression profiles of vGLUT1 in different models of epilepsy. Although these data might suggest an important involvement of this transporter protein in the process of epileptogenesis, the alterations might as well result from the hyperexcitability and/or presence of seizures in these animal models.

Methods: 

In the present study, we investigated the seizure susceptibility of vGLUT1 heterozygous (HET) mice and their wild type (WT) littermates in the pilocarpine model for temporal lobe epilepsy and the pentylenetetrazol (PTZ) model for generalized epilepsy. This will allow us to investigate whether a severe reduction in vGLUT1 protein in the HET mice can affect seizure generation and thus whether the vGLUT1 protein is crucially involved in the origin of limbic and/or generalized seizure activity.

Seizure threshold for pilocarpine (i.v.; 24 mg/ml) and PTZ (i.v.; 7,5 mg/ml) were compared in vGLUT1 HET mice and vGLUT1 WT littermates.

Results: 

The threshold doses for pilocarpine that induced rearing, falling, tonic hindlimb extension and death were significantly lower in vGLUT1 HET compared to vGLUT1 WT mice. Similarly, a tendency towards a decreased dose of PTZ was necessary to induce falling, tonic hindlimb extension and death in the vGLUT1 HET animals, compared with their WT littermates, pointing towards a lower resistance to convulsions provoked by PTZ in the vGLUT1 HET animals.

Conclusions: 

These data suggest, for the first time, that vGLUT1 is a transporter that could be involved in generating limbic and generalized seizures.