Epilepsy is a condition of recurrent seizures. In the US alone, there are nearly 500 new cases of epilepsy diagnosed every day, and up to 50,000 epilepsy related deaths annually. Temporal lobe epilepsy is the most common form of epilepsy in adults, and is associated with cognitive decline. For over 40% of patients, seizures are not controlled with current treatment options, and systemic anti-epileptic drugs can have major, negative side-effects. New treatment options are needed. On-demand optogenetics, with real-time, seizure detection triggering the delivery of light to the hippocampus (a key brain structure in temporal lobe epilepsy), can stop spontaneous seizures in a mouse model of temporal lobe epilepsy. These techniques also provide a unique opportunity to investigate the networks critically involved in seizures. This proposal examines the role of cerebellar-hippocampal interactions during seizures and hippocampal-dependent cognition, using on- demand optogenetics, in vivo juxtacellular recordings, and behavioral testing with the intrahippocampal kainate mouse model of temporal lobe epilepsy. By recognizing the ability of the cerebellum to inhibit seizures, and identifying mechanisms through which this is mediated, we not only gain insight into seizures, but also achieve new therapeutic targets and strategies for treating this prevalent and serious disorder. Candidate and Career Summary I am interested in networks and neuronal diversity, and the roles of these in physiological processes and disease. My career goals include becoming an independent researcher, studying epilepsy and disorders which may provide additional insight into epilepsy. Key questions remain in epilepsy research, including what are the key networks and conditions involved in initiating, sustaining, propagating, terminating, and potentially suppressing temporal lobe seizures. By improving our understanding of these, we improve the prospects of someday reaching the goal of no seizures, no side effects, for all epilepsy patients. While my training has equipped me with many of the tools necessary for addressing these questions and becoming a successful independent researcher, the further training received through this K99 provides key additions. Specifically, this K99 will provide 1) training in new techniques, 2) public speaking training, 3) an improved network for collaborations, 4) additional teaching experience, and 5) funding and grant writing training. This additional training and experience provided by the K99 portion, combined with my prior experience, will allow me to establish a successful, independent laboratory working to address fundamental questions of neuronal networks, within and across brain structures, in health and disease.
Epilepsy is a serious disorder of recurrent seizures affecting 65 million people. For 40% of patients, seizures are not controlled by current treatment options, and current treatment options can have major negative side effects. This proposal identifies new potential treatment targets, and improves our understanding of neuronal circuits important for the inhibition of seizures.
|Krook-Magnuson, Esther; Soltesz, Ivan (2015) Beyond the hammer and the scalpel: selective circuit control for the epilepsies. Nat Neurosci 18:331-8|
|Krook-Magnuson, Esther; Gelinas, Jennifer N; Soltesz, Ivan et al. (2015) Neuroelectronics and Biooptics: Closed-Loop Technologies in Neurological Disorders. JAMA Neurol 72:823-9|
|Nagaraj, Vivek; Lee, Steven T; Krook-Magnuson, Esther et al. (2015) Future of seizure prediction and intervention: closing the loop. J Clin Neurophysiol 32:194-206|
|Krook-Magnuson, Esther; Ledri, Marco; Soltesz, Ivan et al. (2014) How might novel technologies such as optogenetics lead to better treatments in epilepsy? Adv Exp Med Biol 813:319-36|
|Krook-Magnuson, Esther; Szabo, Gergely G; Armstrong, Caren et al. (2014) Cerebellar Directed Optogenetic Intervention Inhibits Spontaneous Hippocampal Seizures in a Mouse Model of Temporal Lobe Epilepsy. eNeuro 1:|