A newly identified mice model could serve as an accurate simulation of Lennox-Gastaut syndrome (LGS), according to a study recently published in Molecular and Cellular Mechanisms of Epilepsy.
“We find it particularly important to study mutants of genes encoding GABAAR subunits, since these tend to directly impair inhibitory neurotransmission, thus causing a perturbation in the inhibitory and excitatory balance that typically underlies epileptic seizures,” the authors wrote.
This experimental study aimed to evaluate if the Gabrb3+/N328D knock-in mice could mimic the pathophysiology of LGS. The researchers developed mice with heterozygous expression of the Gabrb3 gene: c.A982G and p.N238D, corresponding to a novel mutation recently associated with LGS.
Read more about LGS etiology
The study later quantified the expression of the GABA-A receptor subunit through Western blot. Also, they recorded the presence of seizure activity and signs of cognitive impairment using video-monitored electroencephalogram (EEG) and behavioral tests, respectively.
After observing spontaneous seizures among the Gabrb3+/N328D mice, as well as impaired spatial learning, memory, and locomotion, the investigators determined that this model successfully mimics LGS. Also, the mice exhibited lower beta-3 subunit expression in 3 different central nervous system structures: the cerebellum, hippocampus, and thalamus.
Moreover, the mice had overexpression of ubiquilin-1, a protein that makes possible the interaction between the ubiquitin protease system and GABA-A receptors. This finding will allow future research on ubiquilin-1 as a potential therapeutic target. Previous analyses in the literature have described that greater expression of ubiquilin-1 could decrease seizure activity by allowing the clearance of mutant proteins involved in the trafficking pathway that usually accumulate in patients with LGS.
“We hypothesize that overexpression of this protein can rescue the developmental and epileptic phenotype through exploiting both the chaperoning and recycling capabilities of Plic-1, and this is an exciting direction of therapeutic development for LGS that employs the Gabrb3+/N328D mouse in our future study,” the authors concluded.
Reference
Ikemefuna G, Shen W, Zavalin K, et al. GABAA receptor β3 subunit Mutation N328D heterozygous knock-in mice have Lennox–Gastaut syndrome. Int J Mol Sci. Published online May 8, 2023. doi:10.3390/ijms24098458
