Glutamine synthetase (GS) is a pivotal glial enzyme in the glutamate-glutamine cycle. GS is important in maintaining low extracellular glutamate concentrations and is down-regulated in the hippocampus of temporal lobe epilepsy patients with mesial-temporal sclerosis, an epilepsy syndrome which is frequently associated with early life febrile seizures (FS). Human congenital loss of GS activity has been shown to result in brain malformations, seizures and death within days after birth. Recently, we showed that GS knockout mice die during embryonic development and that haploinsufficient GS mice have no obvious abnormalities or behavioral seizures. In the present study we investigated whether reduced expression/activity of GS in haploinsufficient GS mice increased the susceptibility to experimentally induced FS.