West syndrome is the most common of the catastrophic epilepsies of early childhood. Onset is most often within the first year of life and babies with this disorder have very brief seizures (only a few seconds in duration) – thus the coining of the alternate name infantile spasms. The epileptic spasms commonly occur in clusters of up to 100 in a few minutes. The spasms, along with the highly chaotic EEG patterns called hypsarrhythmia, are thought to contribute to the severe intellectual disabilities seen in most children. Indeed neurodevelopmental arrest or regression is frequently observed upon spasm onset. Other neurobehavioral comorbidities evolve as well including hyperactivity. In terms of treatments, ACTH and vigabatrin are FDA approved to stop the spasms and are effective in ~ 50% of children. However, both drugs can produce serious side effects. More importantly, while these drugs can eliminate spasms in some children, most often the neurobehavioral comorbidities persist and are life-long. Thus treatments are needed that will not only stop the spasms but also prevent the intellectual disabilities and other neurobehavioral deficits. Recent large multicenter clinical trials have reported more optimistic outcomes. They suggest that prompt diagnosis and rapid elimination of spasms can result in improved neurobehavioral outcomes. For instance, outcomes are better if treatment is initiated within 1 week of diagnosis rather than 2 months. These results and others like them have led to a position statement endorsed by the Child Neurology Society and American Epilepsy Society that prompt treatment of epileptic spasms is essential in order to prevent worse developmental and intellectual outcomes. In this application, we propose to establish the TTX animal model of infantile spasms for the discovery of new treatments to prevent neurobehavioral comorbidities. The model already has good external validity. In addition, preliminary results reported here indicate that animals with spasms have learning and memory deficits and an accompanying hyperactivity phenotype. We propose 4 specific aims. In the first, we will fully characterize the learning and memory deficits and hyperactivity phenotype in these animals. In the second, we will establish the best dosing for a novel combination therapy of vigabatrin and the neuroactive peptide (1-3)IGF-1 that synergies with vigabatrin to enhance GABAergic synaptic transmission and rapidly eliminates spasms in a large majority of animals. In the third and fourth aims, we will establish the predictive validity of the model by treating rats with the combination therapy and showing that early elimination of spasms and hypsarrhythmia will ameliorate neurobehavioral comorbidities but delayed treatment will not. If successful, these studies will establish the TTX model as a much-needed tool for discovering less toxic and more effective new therapies, which will significantly improve long-term outcomes for children with this ...