Infantile spasms (IS, also known as West Syndrome) is a catastrophic childhood epilepsy syndrome characterized by spasms which progress into seizures later in life. Spasms are typified by spontaneous flexion/extension of the head, neck, and limbs and occur first between 4 and 8 months of age. The current treatment options for IS are often ineffective and are associated with significant side effects. Therefore, novel treatment strategies are essential. One limiting factor in identifying new treatment approaches is a paucity of pre-clinical animal models. We have identified and characterized a novel rodent model with many phenotypic characteristics of human IS. The model was generated by breeding male mice containing a floxed version of the Adenomatous polyposis coli (APC) gene with female mice expressing the Cre-recombinase gene under the control of the Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIa) promoter. The offspring of this cross, which lack APC in CaMKIIa-positive neurons, are known as APC conditional knockouts (APC cKOs). APC cKO animals have been shown to have increased excitatory synaptic communication and an increased density of excitatory spines on hippocampal CA1 pyramidal neurons. APC is the main inhibitory regulator of a large signaling pathway known as the ?-catenin/Wnt pathway. APC is part of the ?-catenin destruction complex, targeting ?-catenin for degradation. When APC is lost, ?-catenin levels rise and 1) increase transcription of a large family of genes, and 2) increase the stability of excitatory synapses. We began by examining APC cKO animals for phenotypes consistent with human IS. We found that they exhibit spontaneous behavioral spasms at postnatal days 8-11, they have an ictal EEG correlate of spasm behavior similar to human ictal activity in IS, and as adults, they have spontaneous electrographic and behavioral seizures. Interestingly, APC heterozygous mutations in humans are linked to both developmental and seizure disorders. Furthermore, many of the genes linked to IS are either part of the ?-catenin/Wnt pathway or are reciprocally regulated by it. In this proposal, we will specifically examine the role of ?-catenin in the pathophysiology of infantile spasms. We will examine the effects of increasing ?-catenin (by deleting APC and independently of APC) on spasm behavior, seizures, and electrographic brain activity. Next, we will perform careful pharmacokinetic, pharmacodynamic, and adverse effect analysis of manipulating ?-catenin during development with a drug called G007-LK. Lastly, we will determine if restoring ?-catenin levels to normal attenuates spasms and seizures later in life. This proposal will address the role of ?-catenin in the pathophysiology of spasms, provide a new mouse model for pre-clinical analysis, and introduce a large set of new potential therapeutic targets for the treatment of IS.
Infantile spasms are a devastating form of childhood epilepsy which leads to lifelong developmental delays and immeasurable consequences for children and their families. The underlying causes of infantile spasms are largely unknown, and current treatment options are far from ideal. Here we identify a new molecule, ?-catenin, which may be implicated in infantile spasms, and examine strategies to utilize ?-catenin as a new therapeutic target.
| Dulla, Chris G (2018) Utilizing Animal Models of Infantile Spasms. Epilepsy Curr 18:107-112 |
