Mice carrying a de novo mutation identified in a patient with Lennox-Gastaut syndrome (LGS) have a phenotype and neurological impairment resembling the disease, a new study published in the International Journal of Molecular Sciences reported. These mice could, therefore, be a good model to investigate the pathophysiology of the disease as well as test the efficacy of new potential therapies.
Read more about the pathophysiology of LGS
This finding is important because the pathophysiology of LGS is not well known and there are only a few animal models to study the disease.
In cases where there are no underlying pathological causes, LGS may be associated with genetic mutations in certain genes including GABRB3, which codes for the β3 subunit of the GABAA receptor.
In the present study, a team of researchers led by Jing-Qiong Kang, MD, PhD, from Vanderbilt University and Vanderbilt Brain Institute in Nashville, Tennessee developed a heterozygous knock-in mouse model expressing GABRB3 that carries a de novo mutation identified in a patient with LGS (Gabrb3+/N328D mice).
The team then examined the Gabrb3+/N328D mice for features of the disease.
They found that 2- to 4-month-old male and female mice developed spontaneous seizures and signs of cognitive impairment. These impairments included deficits in spatial learning, memory, and locomotion.
In addition, the Gabrb3+/N328D mice had reduced expression of the GABAA receptor β3 subunit in the cerebellum, hippocampus, and thalamus.
“This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype,” the researchers wrote.
LGS is a rare and severe type of childhood epilepsy characterized by multiple seizure types including tonic, generalized tonic-clonic, atonic, atypical absence, and myoclonic, which are highly refractory to antiepileptic drugs. The onset of seizures is usually during the first decade of life and is most common among children aged 3 to 5 years.
Nwosu GI, 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