Studies of Mechanisms of Epilepsy and Therapeutics, including
Pharmacologic and Dietary Interventions
Tim Simeone, PhD
We are interested in the synaptic, cellular and network mechanisms of hyprexcitability and hypersynchrony that underlie the generation and propagation of seizures. Identifying such mechanisms will lead to development of viable therapeutic targets and have relevance for understanding other neurological disorders, sleep and cognitive processes. Our approach is to examine processes, the consequences of disease and the effects of therapeutics from the level of the whole animal all the way down through networks, synapses, single cells, mitochondria and genetics and back up to the whole animal. One strategic focus has been to determine and understand the effects of the ketogenic dietary treatment for refractory epilepsy. Using this knowledge we have recently identified a number of gene products critical for the antiseizure efficacy of the ketogenic diet, and hitherto of unknown importance for maintaining cellular homeostasis in the brain.
Currently, projects focus on:
Mechanism of action of the ketogenic diet, related to seizure control, cellular and synaptic activity and mitochondrial function.
The role of the transcription factor PPARgamma in epilepsy: upstream regulators and downstream effectors.
Mitochondrial regulation of synaptic activity.
The importance of sharp wave/high frequency oscillations in hippocampal function and dysfunction.
The role of peripheral adaptive immunity in epilepsy.
Development of novel animal models for epilepsy.
Defining the pharmacoresponsiveness of known epilepsy models.
The laboratory uses a wide range of experimental techniques including:
Use of genetic and pharmacologic models to dissect gene function in epilepsy and therapeutics.
In vivo video-EEG recordings to evaluate seizures and sleep.
In situ electrophysiology in living brain slices
patch clamp recordings from individual neurons
multi-electrode array extracellular recordings of neuronal network population activity and individual neuronal activity
Immunohisotchemical techniques for cell identification and protein isolation.
Molecular biology techniques including western blots for protein quantification and RT-qPCR for gene transcript quantification.
Flow cytometry for immune cell identification.
Dinner with friend and mentor Karen Wilcox. American Epilepsy Society 2017.
American Epilepsy Society 2017 Co-Chairs Drs. Amy Kao and Tim Simeone.