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The Journal of Neuroscience, June 1, 2002, 22(11):4591-4599
Developmental Febrile Seizures Modulate Hippocampal Gene
Expression of Hyperpolarization-Activated Channels in an Isoform-
and Cell-Specific Manner
Amy
Brewster1, *,
Roland
A.
Bender1, 2, *,
Yuncai
Chen2,
Celine
Dube1,
Mariam
Eghbal-Ahmadi2, and
Tallie Z.
Baram1, 2, 3
Departments of 1 Anatomy/Neurobiology,
2 Pediatrics, and 3 Neurology, University of
California at Irvine, Irvine, California 92697-4475
Febrile seizures, in addition to being the most common seizure type
of the developing human, may contribute to the generation of subsequent
limbic epilepsy. Our previous work has demonstrated that prolonged
experimental febrile seizures in the immature rat model increased
hippocampal excitability long term, enhancing susceptibility to future
seizures. The mechanisms for these profound proepileptogenic changes
did not require cell death and were associated with long-term slowed
kinetics of the hyperpolarization-activated depolarizing current
(IH). Here we show that these
seizures modulate the expression of genes encoding this current, the
hyperpolarization-activated, cyclic nucleotide-gated channels (HCNs):
In CA1 neurons expressing multiple HCN isoforms, the seizures induced a
coordinated reduction of HCN1 mRNA and enhancement of HCN2 expression,
thus altering the neuronal HCN phenotype. The seizure-induced
augmentation of HCN2 expression involved CA3 in addition to CA1,
whereas for HCN4, mRNA expression was not changed by the seizures in
either hippocampal region. This isoform- and region-specific
transcriptional regulation of the HCNs required neuronal activity
rather than hyperthermia alone, correlated with seizure duration, and
favored the formation of slow-kinetics HCN2-encoded channels. In
summary, these data demonstrate a novel, activity-dependent
transcriptional regulation of HCN molecules by developmental seizures.
These changes result in long-lasting alteration of the HCN phenotype of
specific hippocampal neuronal populations, with profound consequences
on the excitability of the hippocampal network.
Key words:
hippocampus; development; febrile seizures; epilepsy; channels; hyperpolarization; HCN; neuroplasticity
*
A.B. and R.A.B. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22114591-09$05.00/0
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