Epilepsy, particularly pediatric epilepsy, is associated with a very high incidence of cognitive, behavioral and psychiatric comorbidities that are often more detrimental to overall quality of life than the seizures themselves. Aggressive treatment of seizures has been the gold standard, with the belief that this will also minimize cognitive and psychiatric comorbidities. However, very little focus has been placed on treatment of these comorbidities directly and clinical data suggest that focusing on seizure treatment alone does not effectively treat cognitive impairment. We have recently found that ACTH, an endogenous part of the hypothalamic- pituitary-adrenal axis that is often exogenously administered to children with severe epilepsies, can improve cognitive outcome in rats without altering seizure parameters. While it was previously thought that the primary mechanism of action for ACTH was through the release of corticosteroids, new research suggests that melanocortin 4 receptor (MC4R) activation in neuronal and glial populations is neuroprotective and can improve outcomes in other disease models. We hypothesize that MC4R agonism in the CNS with ACTH is a key mechanism of action by which it can improve cognitive outcomes after early life seizures (ELS). We further hypothesize that early treatment with ACTH will normalized functional organization of neural networks within and between the prefrontal cortex and the hippocampus, and that this improvement will provide a systems-level mechanism underpinning its mechanism of action. Understanding how ACTH can prevent cognitive deficits without altering seizure parameters is crucial for finding novel treatment approaches for these deficits. Therefore, the scientific aims of this study are to: 1) (Phase I) determine the role of MC4R signaling in the brain on subsequent cognition in control animals and (Phase II) ELS animals, 2) (Phase I) determine the effect of early treatment with ACTH on synaptic plasticity in adult neuronal networks in the PFC after ELS and finally 3) (Phase II) determine the effect of early treatment with ACTH on adult neuronal networks in vivo and executive dysfunction associated with ELS. To achieve these goals, I require additional training, both formal through a ?Methods in Computational Neuroscience? course at the Marine Biological Laboratory and informal with my co-mentor, Dr. Mahoney, in order to develop the neurocomputational modeling tools necessary for exploring the systems-level mechanisms of cognitive impairment after ELS and the prevention of such impairments with ACTH. The studies proposed are designed to understand the developmental role of ACTH and MC4Rs on cognitive networks in ELS. Successful completion of this project has the potential to change the way we think about treatment of pediatric epilepsy, and may have implications for the treatment of other neurodevelopmental disorders as well.
I am proposing to study the mechanism underlying the effectiveness of ACTH (a drug given to patients with severe forms of pediatric epilepsy) in the prevention of cognitive deficits associated with early life seizures in a rodent model. The results of these experiments have significant clinical relevance, as they will elucidate the role of a novel signaling pathway that may be used as a therapeutic target for cognitive deficits associated with pediatric epilepsy as well as other neurodevelopmental disorders.