Effect of ceftriaxone on the glutamate-glutamine cycle and seizure susceptibility of Tg2576 mouse model of Alzheimer's disease.

Background: Individuals with Alzheimer's disease (AD) have a heightened risk of epilepsy. However, the underlying mechanisms are not well-understood.

Objective: We aimed to elucidate the role of the glutamate-glutamine cycle in this mechanism and test the effect of ceftriaxone, a glutamate transporter-1 (GLT-1) enhancer, on seizure susceptibility in the Tg2576 mouse model of AD.

Methods: First, we assessed expression levels of key proteins in the glutamate-glutamine cycle in Tg2576 ( = 7) and wild-type littermates ( = 7), and subsequently in the kindling model of epilepsy ( = 6) and sham ( = 6). Then, kindling susceptibility was assessed in three groups: 200 mg/kg ceftriaxone-treated Tg2576 (Tg-Ceft,  = 9); saline-treated Tg2576 (Tg-Sal,  = 9); and saline-treated wild-type (WT-Sal,  = 15). Mice were treated for seven days before kindling, and seizure susceptibility compared between groups.

Results: Protein levels of GLT-1 ( = 0.0093) and glutamine synthetase ( = 0.0016) were reduced in cortex of Tg2576 mice, compared to WT. Kindling increased GLT-1 (cortex:  < 0.0001, hippocampus:  = 0.0075), and glutaminase (cortex:  = 0.0044) protein levels, compared to sham. Both Tg-Ceft and WT-Sal displayed Class IV seizures in response to the first stimulation ( > 0.99), while Tg-Sal displayed Class V seizure ( = 0.0212 versus WT-Sal). Seizure susceptibility of Tg-Ceft was not different from Tg-Sal ( > 0.05), and kindling rates did not differ between groups.

Conclusions: Disruptions to key components of the glutamate-glutamine cycle are observed in models of AD and epilepsy. However, increasing GLT-1 through ceftriaxone treatment did not influence seizure susceptibility in Tg2576 mice, suggesting this is not an effective strategy to lower seizure susceptibility in AD, or a higher dosage is needed.