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Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability

Abstract

Febrile seizures are the most common type of developmental seizures, affecting up to 5% of children. Experimental complex febrile seizures involving the immature rat hippocampus led to a persistent lowering of seizure threshold despite an upregulation of inhibition. Here we provide a mechanistic resolution to this paradox by showing that, in the hippocampus of rats that had febrile seizures, the long-lasting enhancement of the widely expressed intrinsic membrane conductance Ih converts the potentiated synaptic inhibition to hyperexcitability in a frequency-dependent manner. The altered gain of this molecular inhibition–excitation converter reveals a new mechanism for controlling the balance of excitation–inhibition in the limbic system. In addition, here we show for the first time that h-channels are modified in a human neurological disease paradigm.

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Figure 1: Long-lasting shift in h-current activation following hyperthermia-induced seizures.
Figure 2: Kinetic changes in Ih following seizures and the effect of modulation of intracellular cAMP.
Figure 3: Enhanced activation of altered Ih by hyperpolarizing inputs and post-inhibitory rebound firing following hyperthermia-induced seizures.
Figure 4: Mechanism of post-inhibitory rebound firing, specificity of the changes affecting Ih, and pattern of spontaneous GABA-receptor activation after febrile seizures.
Figure 5: Multicompartmental modeling shows importance of altered h-channels in limiting inhibitory inputs and generating post-inhibitory rebound firing.

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Acknowledgements

We thank R. Zhu for technical assistance. This work was financially supported by the NIH (NS38580 to I.S. and NS35439 to T.Z.B.), by the UC Systemwide Biotechnology Research and Education Program (BREP-98-02 to T.Z.B. & I.S.) and by a Postdoctoral Fellowship from the Epilepsy Foundation of America (to I.A.).

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Correspondence to Ivan Soltesz.

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Chen, K., Aradi, I., Thon, N. et al. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med 7, 331–337 (2001). https://doi.org/10.1038/85480

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