Abstracts

Rationale: Infantile spasms (IS) constitute a catastrophic childhood epilepsy syndrome characterized by neonatal rapid flexion and extension spasms, which progress to severe developmental and cognitive deficits and a lifetime of seizures. The underlying molecular and functional changes that cause IS are poorly defined and animal models remain sparse. Current treatments have mixed efficacy and severe side effects. The identification of the pathophysiological changes is critical to developing effective therapeutic interventions. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter ߭catenin/ Wnt signaling pathways, these pathways are critical for the normal formation and function of brain circuits. Here we show that excessive ߭catenin/ Wnt signaling can lead to IS-like spasms and seizures. Methods: We generated two different mouse lines with elevated ߭catenin in neurons. In one line, we conditionally deleted adenomatous polyposis coli protein (APC cKO), the major negative regulator of ߭catenin levels. In the other mouse line, we conditionally deleted the phosphorylation site required for targeting ߭cat to the degradation complex, generating a ߭cat conditional overexpressor (cOE). Results: APC cKOs display excessive ߭catenin, altered expression of Wnt target genes and most of the features of human IS. Neonatal APC cKOs exhibit robust flexion-extension spasms and abnormal neonatal electroencephalographic (EEG) activity. At adult ages, APC cKOs display spontaneous electrographic seizures. Similarly, our novel mouse model ߭cat cOE also leads to excessive ߭catenin levels and IS-like phenotypes (neonatal spasms and chronic seizures). We prevented the excessive ߭catenin levels by conditional deletion of both APC and ߭catenin alleles (APC/߭cat double cKOs). The double APC, ߭catenin cKOs do not develop spasms or seizures. These findings implicate aberrant levels of ߭catenin as a key pathophysiological change that can lead to IS-like phenotypes. Our preliminary studies suggest structural and circuit connection changes. Both APC cKO and ߭cat cOE mice show increases in synaptic spine density, abnormal plasticity of excitatory synapses, and changes in cortico-striatal connections, with increased excitatory inputs to striatal neurons. Conclusions: Our data provide the first in vivo evidence for a novel molecular etiology of IS that is centered on aberrant ߭catenin networks. We propose ߭catenin as a new molecular target for effective therapeutic interventions to ameliorate spasms and seizures. Funding: Cure, Infantile Spasms initiative