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Epilepsy: Error of Scales? Ann Arbor, MI 2007 PowerPoint Presentation
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Epilepsy: Error of Scales? Ann Arbor, MI 2007

Epilepsy: Error of Scales? Ann Arbor, MI 2007

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Epilepsy: Error of Scales? Ann Arbor, MI 2007

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  1. Epilepsy: Error of Scales?Ann Arbor, MI 2007 Theoden Netoff University of Minnesota, BME

  2. 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

  3. 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. Ih modulation following a Seizure:two models, two different results

  4. Ih: Hyperpolarizing activated cationic current. The “Sag” current Chen and Soltesz

  5. Opposing effects of Ih Santoro and Baram The multiple personalities of h-channels. TINS 26(10)550:554

  6. 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 Iapp Vm

  7. T Phase Response Curve

  8.  Phase Response Curve

  9. Phase Response Curve

  10. Phase Response Curve Excitatory Input Type 1 Type 2

  11. Predicted excitatory interaction - =

  12. Fixedpoints of Spike time difference map (STDM)

  13. Measuring from Neurons

  14. STRCs measured and network behaviors.

  15. Effects of Ih on PRC and network synchrony W/o added Ih W/ added Ih No Ih, Added Ih PRC STDM STDH

  16. Effects of Ih on two cell networks W/ Ih W/o Ih

  17. Spike time differences w/o Ih

  18. Spike time differences w/ Ih

  19. Network Hypothesis • Raising Ih or lowering Ih may depend on whether activity is caused by feedforward or feedback network activity ↑ Activity ↓ Ih ↑ Activity ↑ Ih

  20. Homeostatic effects of changing Ih • Increasing Ih ↓ synaptic efficacy • ↓ in efficacy early in spiking phase • Phase dependent ↓ makes network ↑ synchrony • In Hippocampus: • ↑ Ih ↓ activity because it is a feedforward network (CA3→CA1) and dampens network input. • In Entorhinal cortex: • ↑ Ih ↑ activity because it is a feedback network by synchronizing the excitatory cells

  21. 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?

  22. John White Nancy Kopell Jonathan Bettencourt Alan Dorval Brian Burton Acknowledgements • Grants: • Postdoctoral NRSA: • 5F32MH066555-02 • Fellowships: • Center for BioDynamics (Boston University)