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Epilepsy: Error of Scales? Ann Arbor, MI 2007 Theoden Netoff University of Minnesota, BME
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Homeostasis and Epilepsy Neurons are in constant state of flux There is no single solution of ion channel densities to achieve a particular behavior There are many changes in response to an event like a seizure: –Changes in ion channel densities –Changes in neuronal dynamics –Changes in network coupling
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I h modulation following a Seizure: two models, two different results Shah and Johnston –Kanic acid injection. –EC Layer III Pyramidal Neurons –Decreased Ih density in dendrites –Hypothesis: Decreasing Ih increases synaptic efficacy and increases excitability of the cells. Chen and Soltesz –Febrile seizures –CA1 Pyramidal Cells –Increase in Ih current –Hypothesis: Increasing Ih causes rebound excitation following inhibition.
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I h : Hyperpolarizing activated cationic current. Chen and Soltesz The “Sag” current
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Opposing effects of Ih Santoro and Baram The multiple personalities of h- channels. TINS 26(10)550:554
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Dynamic clamp Computer controlled delivery of current to a cell Complex protocols Simulation of ion channels Simulation of synapses Simulation of neurons to make “hybrid” networks V m I app
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Phase Response Curve T
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Type 1Type 2 Excitatory Input
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Predicted excitatory interaction - =
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Fixedpoints of Spike time difference map (STDM)
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Measuring from Neurons
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STRCs measured and network behaviors.
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Effects of Ih on PRC and network synchrony W/o added IhW/ added Ih No Ih, Added Ih PRC STDM STDH
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Effects of Ih on two cell networks W/o Ih W/ Ih
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Spike time differences w/o I h
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Spike time differences w/ I h
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Network Hypothesis Raising Ih or lowering Ih may depend on whether activity is caused by feedforward or feedback network activity ↑ Activity ↓ Ih ↑ Activity ↑ Ih
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What are the implications to these findings? Hyp: Induction of epilepsy caused by a homeostatic response that results in an unstable solution. 1)Lots of network synchrony 1)Response- decrease Ih to decrease synchrony 2)Results in increased hyperexcitability 2)Lots of network activity 1)Response- increase Ih to decouple cells 2)Response- increase inhibition. 3)Results- increased rebound excitation. 4)Results- in increased synchrony.
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Paradoxical effects of I h Decreases response to synaptic input Causes network to synchronize better In Hippocampus: –↑ I h ↓ activity because it is a feedforward network (CA3→CA1) and dampens network input. In Entorhinal cortex: –↑ I h ↑ activity because it is a feedback network by synchronizing the excitatory cel
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Homeostatic effects of changing I h Increasing I h ↓ synaptic efficacy ↓ in efficacy early in spiking phase Phase dependent ↓ makes network ↑ synchrony In Hippocampus: –↑ I h ↓ activity because it is a feedforward network (CA3→CA1) and dampens network input. In Entorhinal cortex: –↑ I h ↑ activity because it is a feedback network by synchronizing the excitatory cells
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Question: Homeostatic mechanisms work at the level of the individual neuron. Is epilepsy be caused by discrepancies between homeostatic mechanisms at the cellular and their actions at a network scale?
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Acknowledgements John White Nancy Kopell Jonathan Bettencourt Alan Dorval Brian Burton Grants: Postdoctoral NRSA: 5F32MH066555-02 Fellowships: Center for BioDynamics (Boston University)
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