The glutamate transporter 1 (GLT-1) could become a novel therapeutic target for patients with Dravet syndrome (DS), according to a study recently published in the Annals of Clinical and Translational Neurology.
“In summary, our findings indicate that GLT-1/excitatory amino acid transporter type 2 (EAAT2) expression may be a viable therapeutic target in DS and underscore that modulation of background neurobiology elements can be considered in complement to treating the primary deficit in the genetic epilepsies,” the authors wrote.
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This experimental study tested cortical GLT-1 protein expression in SCN1A haploinsufficient mouse DS models. The mice on the F1 hybrid (C57x129S) background showed a less severe epileptic phenotype, while mice on the C57 background developed spontaneous seizures. Both strains exhibited reduced GLT-1 expression, suggesting its relevance in disease progression.
To further explore GLT-1 expression, the researchers measured baseline GLT-1 in wild-type mice of all 3 strains. They found that GLT-1 expression varied between the mouse background strains, indicating its potential impact on SCN1A mutation severity.
“Yet we see almost identical reductions in GLT-1 expression in both F1 and 129S SCN1A+/− mice, indicating that reduced GLT-1 expression may be an endophenotype of SCN1A haploinsufficiency itself,” the authors explained.
Moreover, GLT-1 protein expression was reduced in SCN1A haploinsufficient mice, supporting the hypothesis that depressed GLT-1/EAAT2 may contribute to DS. The study opens new possibilities for improving seizure control in patients with DS by upregulating GLT-1/EAAT2.
DS is a severe infantile-onset epileptic encephalopathy associated with mutations in the SCN1A gene. Specifically, the GLT-1 is crucial for glutamate homeostasis, and reduced GLT-1 expression leads to excess excitatory signaling and seizures. Despite recent US Food and Drug Administration approvals for DS drugs, complete seizure suppression remains elusive.
Although this study represents important advances in treating DS, some details are still yet to be fully understood. The question remains whether reduced GLT-1 expression leads to recurrent seizures or if recurrent seizures depress GLT-1 expression. Future experiments and therapeutic trials will aim to answer this important question and determine if GLT-1 upregulation can prevent seizure onset or mitigate established seizures.
Reference
Hameed M, Hui B, Lin R, et al. Depressed glutamate transporter 1 expression in a mouse model of Dravet syndrome. Ann Clin Transl Neurol. Published online July 14, 2023. doi:10.1002/acn3.51851
