Knockin’ Out the Spasms

Commentary During the past 10 years, a great many articles have been written on the animal models of infantile spasms. In fact, a PubMed search for “infantile spasms model” with limitation to “other animals” (to avoid human studies) returns 51 references, out of which 40 have been published since 2007. This is good: Not only do infantile spasms represent a hard-to-treat epilepsy syndrome of infancy, but this syndrome is devastating for both the patient and the family (1). Additionally, our knowledge of the disorder’s neurobiology is evolving quite slowly. Currently, there are several rodent models of infantile spasms available reproducing more or less human symptomatology and treatment response. In normal or abnormal brain, these models utilize a specific trigger of spasms with either an acute or a delayed response (occurrence of spasms) or they are based on a genetic condition (2). While this may seem broad, this approach to the infantile spasms model somewhat recapitulates the human condition: There are more than 200 (and counting) different etiologies responsible for symptomatic infantile spasms, such as those with identifiable brain damage (3). There is also a second major group of cryptogenic infantile spasms (without identifiable brain damage) likely due to yet unknown genetic or epigenetic conditions (4). Any new model is appreciated when it brings more understanding into this quite diverse and peculiar syndrome, where various etiologies eventually merge into a common pathway (5) involving the triad of infantile spasms of similar semiology (spastic seizures), electrographic signature (interictal hypsarhythmia), and developmental regression (mental deterioration). The authors of the current study thoroughly reviewed genes linked to the increased risk of infantile spasms in humans (6–8) and found that 11 out of 15 genes described in the human studies are involved in regulation of b-catenin pathways in the brain, stressing the importance of b-catenin regulation for infantile spasms. Besides the role in cadherin synaptic adhesion, b-catenin also controls Wnt signal transduction. An increase in b-catenin signaling alters brain development and function in favor of more complex dendritic branching and changes of synaptic maturation with increased excitatory synapse density (9). The authors then decided to study the adenomatous polyposis coli (APC) gene linked to five risk genes for infantile spasms. This gene encodes a tumor suppressor protein acting as an antagonist of the Wnt signaling pathway with high concentration in the brain. Moreover, APC serves as an mRNA binding protein with b-catenin as one of its targets. The authors have already created conditional APC knock-out (APC cKO) mice in Ca/calmodulin-dependent protein kinase II-a positive neurons, resulting in loss of control of b-catenin levels. In addition to elevated β-catenin levels in the brain, mice with APC cKO exhibit learning deficits and autismlike behaviors (10). In this study, the mice were investigated using multiple complementary techniques for occurrence of spasms during infancy, seizures during adulthood, EPSCs in APC Conditional Knock-Out Mouse is a Model of Infantile Spasms With Elevated Neuronal β-Catenin Levels, Neonatal Spasms, and Chronic Seizures.