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Volume 16, Number 12,
Issue of June 15, 1996
pp. 3827-3836
Copyright ©1996 Society for Neuroscience
Null Mutation of c-fos Impairs Structural and
Functional Plasticities in the Kindling Model of Epilepsy
Received Jan. 23, 1996; revised March 25, 1996; accepted April 2, 1996.
Yoshinori Watanabe1,
Randall S. Johnson2,
Linda S. Butler1,
Devin
K. Binder3,
Bruce M. Spiegelman2,
Virginia E. Papaioannou4, and
James O. McNamara1, 3, 5
1 Department of Medicine (Neurology), Epilepsy Research
Laboratory, Duke University Medical Center, Durham, North Carolina
27710, 2 Dana-Farber Cancer Institute, Departments of
Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, Massachusetts 02115, 3 Departments of
Neurobiology and Pharmacology, Duke University Medical Center, Durham,
North Carolina 27710, 4 Department of Genetics and
Development, College of Physicians and Surgeons, Columbia University,
New York, New York 10032, and 5 Veterans Affairs
Medical Center, Durham, North Carolina 27705
It has been suggested that expression of the immediate early gene
c-fos links fleeting changes in neuronal activity to lasting
modifications of neuronal structure and function in the mammalian
nervous system. To test this idea, we examined behavioral and
electrophysiological indices of kindling development and
kindling-induced sprouting of hippocampal granule cell axons in
wild-type (+/+), heterozygous (+/ ), and homozygous (/) mice
carrying a null mutation of c-fos. The rate of kindling
development was significantly attenuated in / compared with +/+
mice, as evidenced by both electrophysiological and behavioral
measures. Kindling-induced granule cell axon sprouting as measured by
the Timm stain was also attenuated in homozygous null mutants compared
with +/+ mice, with an intermediate effect in +/ mice. The impairment
of kindling-induced axonal sprouting in the null mutants could not be
attributed to either detectable loss of dentate hilar neurons or
reduced activation of the dentate granule cells by seizures. Instead,
our data are consistent with the hypothesis that the null mutation of
c-fos attenuates a pathological activity-determined
functional plasticity (kindling development) as well as a structural
plasticity (mossy fiber reorganization). We favor the hypothesis that
this ``fos-less phenotype'' is attributable to impaired
seizure-induced transcriptional activation of one or more
growth-related genes.
Key words:
c-fos;
immediate early genes;
kindling;
axonal
reorganization;
epilepsy;
plasticity
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