Abstracts

Rationale: Early infantile epileptic encephalopathies (EIEEs) are a group of devastating pediatric neurological disorders, manifesting with aggressive seizures and significant neurological comorbidities, such as sensory, motor, cognitive, and psychiatric deficits. The treatment options for these catastrophic pediatric epilepsies are very limited, as the current antiepileptic drugs are often ineffective. This is mainly because few valid animal models of EIEEs are available and the underlying pathogeneses remain elusive, which hinders the development of new therapeutic interventions. Heterozygous mutations in the gene encoding syntaxin binding protein 1 (STXBP1) are one of most frequent genetic causes of EIEEs. STXBP1 regulates neurotransmitter release at both excitatory and inhibitory synapses, but how STXBP1 mutations cause epileptic seizures and behavioral deficits remains unknown. Thus, our goal is to develop valid mouse models of STXBP1-related EIEEs and understand the pathogeneses at the molecular, cellular, neural circuit, and behavioral levels. Methods: To model STXBP1-related EIEEs in mice, we generated genetically modified Stxbp1 mouse strains. We performed continuous video-EEG recording to measure brain activities and a battery of behavioral tests to examine neurological functions. We also recorded neuronal synaptic activities from acute brain slices to explore excitation and inhibition balance. Results: The characterization of transgenic models showed that Stxbp1 haploinsufficient mutants exhibited key neurological phenotypes of human patients including seizures and cognitive deficits among others. Furthermore, we found that synaptic inhibition, but not excitation, was decreased in Stxbp1 heterozygous mutants, which likely contributes to their cortical hyperexcitability. Conclusions: Our Stxbp1 haploinsufficient mouse models provide a platform to study the underlying mechanisms and potential therapeutic strategies for EIEEs. Funding: The work was supported by Citizens United for Research in Epilepsy and NIH/NINDS 1R01NS100893 (both to Mingshan Xue).