CAREER: Bridging epileptogenic molecular level changes to neuronal network synchrony to reveal basic mechanisms of epilepsy

University Of Minnesota-Twin Cities, Minneapolis MN

Investigators

Abstract

PI: Netoff, Theoden I. Proposal Number: 0954797 The etiologies of pathological behaviors that emerge in networks are especially difficult to diagnose. The causes are usually subtle changes in the dynamics of the nodes that lead to changes in population behavior. These multi-scale problems are very general. Epilepsy is an example of disease where molecular level changes in neurons caused by genetic mutations lead to pathological neuronal activity generating seizures. While there are many hypotheses, very little is known about how and why these mutations cause seizures, which prevents us from developing better treatments. Understanding how synchrony in networks are affected by known epileptogenic mutations and antiepileptic drugs with known molecular effects will provide a model system in which multiple scales may be bridged. A synergistic approach using numerical simulations electrophysiology experiments and computational simulations will be used. Computational models of neurons will be used to predict how epileptogenic mutations and antiepileptic drugs change the phase response curve (PRC) of a neuron. The PRC is a measure of a neuron?s sensitivity to synaptic inputs. From the PRC it is possible to infer how changes caused by epileptogenic mutations and antiepileptic drugs would alter synchrony in a network of neurons. Predictions from the modeling will be tested using dynamic clamp experiments, where a computer running a real-time interface is interfaced to a neuron through a patch clamp amplifier and electrode. Dynamic clamp experiments will be used to measure the effects of epileptogenic mutations (introduced thorough electrical knock-in) and bath applied antiepileptic drugs on the phase response curve of the neuron. Hybrid networks will then be created using the dynamic clamp to simulate synaptic connections between two patch clamped neurons in which effects of epileptogenic mutations and antiepileptic drugs on synchrony will be measured directly. Physiological experiments will be used to provide parameters to run large scale simulations where synchrony will be measured. Preliminary data is presented from simulations and electrophsiological experiments that epileptogenic mutations in voltage gated sodium channels decrease synchrony and antiepileptic drugs increase synchrony. These findings are in contrast to the popular view of epilepsy that epilepsy is caused by hypersynchrony. By developing our understanding of how these mutations and drugs actually work, we may develop new and better approaches to treating this disease. The goal of this proposed research is to test the hypotheses that changes in the dynamics of neurons caused by epileptogenic mutations increase network synchrony, and that the modulation of neurons by drugs that prevent seizures decrease network synchrony. By proving, or disproving these hypotheses, we will understand if developing new drugs or deep brain stimulation to prevent seizures should be optimized to decrease network synchrony. To test this hypothesis we propose the following specific aims: 1) use single cell modeling to identify effects of epileptogenic mutations and antiepileptic drugs on cell dynamics, 2) network modeling to assess the effect of epileptogenic mutations and antiepileptic drugs on network synchrony, and 3) characterize changes in cell dynamics caused by mutation of SCN1A channel using hybrid experiments with real neurons and virtual ion channels. Intellectual Merit: The research proposed here will help elucidate how changes in neuronal dynamics and topology of network connectivity result in pathological neuronal activity such as seizures. How neuron dynamics are affected by epileptogenic mutations and antiepileptic drugs will be discovered to help develop better models of seizures. Effects of known epileptogenic ion channel mutations and antiepileptic drugs on network synchrony will be used to probe the role of neuronal population synchrony in epilepsy. With this knowledge we will develop more rational approaches to treating epilepsy. Broader impact: Electrophysiolgy data acquired will be cataloged in a database available to any scientist interested in analyzing the data. To complete the electrophysiolgical experiment, we will generate many modules for the dynamicclamp which will be made available to the community using the RTXI dynamic clamp. Code developed to run network simulations using CUDA enabled machines for supercomputer performance on a desktop will be made available to the public. Outreach plan includes collaborations with the Bakken museum, the Epilepsy Foundation, the University of Minnesota?s ?Brain U?, its summer high school program ?Exploring Careers in Engineering and Physical Science?, and it?s North Star Alliance Program.