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Epilepsy: Error of Scales? Ann Arbor, MI 2007

Epilepsy: Error of Scales? Ann Arbor, MI 2007. Theoden Netoff University of Minnesota, BME. Homeostasis and Epilepsy. Neurons are in constant state of flux There is no single solution of ion channel densities to achieve a particular behavior

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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)

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