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 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

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.

I h : Hyperpolarizing activated cationic current. Chen and Soltesz The “Sag” current

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

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

Phase Response Curve T

 

Type 1Type 2 Excitatory Input

Predicted excitatory interaction - =

Fixedpoints of Spike time difference map (STDM)

Measuring from Neurons

STRCs measured and network behaviors.

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

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

Spike time differences w/o I h

Spike time differences w/ I h

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

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.

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

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

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?

Acknowledgements John White Nancy Kopell Jonathan Bettencourt Alan Dorval Brian Burton Grants: Postdoctoral NRSA: 5F32MH Fellowships: Center for BioDynamics (Boston University)