Abstracts

Rationale: Infantile spasms (IS) constitute a catastrophic childhood epilepsy syndrome characterized by neonatal spasms, lifelong seizures and cognitive deficits. Current frontline medications have mixed efficacy and cause severe side effects. Developing new effective treatments is essential, but requires knowledge of the underlying molecular and functional changes, and the particular brain regions whose malfunction cause spasms and seizures.  Methods: To gain insights into the pathophysiology, we have developed a new genetically modified mouse model of IS with conditional deletion (cKO) in neurons of adenomatous polyposis coli protein (APC), the major negative regulator of b-catenin/Wnt signaling pathway. APC cKO mice exhibit most of the features seen in individuals with IS (Pirone et al., 2017). Of relevance, the APC, b-catenin, canonical Wnt pathway links to several human IS-risk genes. In particular, missense variants in APC, predicted to be damaging, have been identified in individuals with epileptic encephalopathies (Epi4K Consortium, 2015). These correlations support the importance of elucidating how malfunction of this pathway alters the brain.  Results: Compared with wild-type littermates, APC cKOs display clusters of high amplitude flexion and extension spasms that peak at postnatal day 9, abnormal EEG at both neonatal and adult ages, and progression to chronic seizures (Pirone et al., 2017). APC cKOs also show brain structural changes consisting of corpus callosum agenesis, increases in synaptic spine density on dendrites of glutamatergic neurons of the cortex and hippocampus, as well as aberrant organization of processes and interneuron subtypess in the striatum. Within the APC cKO dorsal striatum at the age of peak spasm intensity (P9),   cortical glutamatergic presynaptic inputs are increased on medium spiny neurons (MSNs).  Consistent with this structural change, P9 MSNs exhibit altered synaptic activity, increases in mEPSC frequency, but no change in amplitude. Interestingly, the developmental timing of the formation and maturation of cortical-striatal connections correlates with the age of IS-like motor spasms in APC cKOs. Cortical-striatal connections function to regulate motor behaviors, and influence the formation of widespread network connections across many brain regions. Conclusions: We propose that malfunction of cortical-striatal circuits underlies spasms and progression to seizures. Our studies are testing this hypothesis to identify particular brain regions and molecular targets with potential for new, specifically targeted therapeutic interventions to prevent spasms and seizures. Funding: CURE; NIH NINDS R56NS094889-01A1 (CD); NIH NIMH R01MH106623 (MJ).