Hyperpolarization-activated cation currents in human epileptogenic neocortex

Authors


Address correspondence to Rudolf A. Deisz, Charité Universitätsmedizin Berlin, Institute for Cell Biology and Neurobiology, Philippstr. 12, 10115 Berlin, Germany. E-mail: rudolf.deisz@charite.de

Summary

Purpose: Hyperpolarization-activated cation currents (IH) play a pivotal role in the control of neuronal excitability. In animal models of epilepsy both increases and decreases of IH have been reported. We, therefore, characterized properties of IH in human epileptogenic neocortex.

Methods: Layer II/III neurons in slices from epilepsy surgery tissues and rat cortex were investigated with whole-cell patch-clamp recordings.

Results: A total of 484 neurons from 96 temporal lobe epilepsy (TLE) tissues and 32 neurons from 8 frontal lobe epilepsy (FLE) tissues were recorded. Voltage-clamp recordings revealed on hyperpolarizing command steps two time- and voltage-dependent inward currents, namely a fast, Ba2+-sensitive current (KIR) and a slowly activating current, namely consisting of two kinetically distinct components sensitive to the established IH blocker ZD7288. Only, the fast component (IH(fast)) of TLE neurons was on average smaller and activated more slowly (density 2.7 ± 1.6 pA/pF; tau 38.4 ± 34.0 ms) than in FLE neurons (4.7 ± 2.3 pA/pF; 16.6 ± 7.9 ms; p < 0.001 for both). Within the TLE tissues the IH(fast) density (averaged per patient) was smaller in cases with numerous annual grand mal seizures (GM; 2.2 ± 0.6 pA/pF) compared to those with few GM (2.8 ± 1.0 pA/pF; p = 0.0184). A similar difference was obtained in the case of complex partial seizures (CPS; many CPS 2.2 ± 0.6 pA/pF; few CPS 2.9 ± 1.0 pA/pF, p = 0.0037).

Discussion: The biophysical properties of IH in cortices from TLE, FLE, and rat tissue suggest a deficit of HCN1 subunits in the human epileptogenic neocortex, which in turn may increase excitability and probability of seizure activity.

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