Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia

Asher J. Albertson, Jianming Yang, John J. Hablitz

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze lesions in newborn rats reproduce many of the anatomical and physiological characteristics of human cortical dysplasia. Rats with freeze lesions have increased seizure susceptibility and a region of hyperexcitable cortex adjacent to the lesion. Since alterations in hyperpolarization-activated nonspecific cation (HCN) channels are often associated with epilepsy, we used whole cell patch-clamp recording and voltage-sensitive dye imaging to examine alterations in HCN channels and inwardly rectifying hyperpolarization-activated currents (I h) in cortical dysplasia. (L5) pyramidal neurons in lesioned animals had hyperpolarized resting membrane potentials, increased input resistances and reduced voltage "sag" associated with I h activation. These differences became nonsignificant after application of the I h blocker ZD7288. Temporal excitatory postsynaptic potential (EPSP) summation and intrinsic excitability were increased in neurons near the freeze lesion. Using voltage-sensitive dye imaging of neocortical slices, we found that inhibiting I h with ZD7288 increased the half-width of dye signals. The anticonvulsant lamotrigine produced a significant decrease in spread of activity. The ability of lamotrigine to decrease network activity was reduced in the hyperexcitable cortex near the freeze lesion. These results suggest that I h serves to constrain network activity in addition to its role in regulating cellular excitability. Reduced I h may contribute to increased network excitability in cortical dysplasia.

Original languageEnglish
Pages (from-to)2189-2200
Number of pages12
JournalJournal of neurophysiology
Volume106
Issue number5
DOIs
StatePublished - Nov 2011

Keywords

  • Epilepsy
  • HCN channel
  • I
  • Voltage-sensitive dye

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