Nonobligate role of early or sustained expression of immediate-early gene proteins c-fos, c-jun, and Zif/268 in hippocampal mossy fiber sprouting.
Axon sprouting in dentate granule cells is an important model of structural plasticity in the hippocampus. Although the process can be triggered by deafferentation, intense activation of glutamate receptors, and other convulsant stimuli, the specific molecular steps required to initiate and sustain mossy fiber (MF) reorganization are unknown. The cellular immediate early genes (IEGs) c-fos, c-jun, and zif/268 are major candidates for the initial steps of this plasticity, because they encode transcription factors that may trigger cascades of activity-dependent neuronal gene expression and are strongly induced in all experimental models of MF sprouting. The mutant mouse stargazer offers an important opportunity to test the specific role of IEGs, because it displays generalized nonconvulsive epilepsy and intense MF sprouting in the absence of regional cell injury. Here we report that stargazer mice show no detectable elevations in c-Fos, c-Jun, or Zif/268 immediate early gene proteins (IEGPs) before or during MF growth. Experimental results in stargazer, including (1) a strong IEGP response to kainate-induced convulsive seizures, (2) no IEGP response after prolongation of spike-wave synchronization, (3) no IEGP increase at the developmental onset of seizures or after prolonged seizure suppression, and (4) unaltered levels of the intracellular Ca2+-buffering proteins calbindin-D28k or parvalbumin, exclude the possibility that absence of an IEGP response in stargazer is either gene-linked or suppressed by known refractory mechanisms. These data demonstrate that increased levels of these IEGPs are not an obligatory step in MF-reactive sprouting and differentiate the early downstream molecular cascades of two major seizure types.
Nahm
W K
WK
Developmental Neurogenetics Laboratory, Department of Neurology, and Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Noebels
J L
JL
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001369:Axons / Q000502:physiology; D001923:Brain Chemistry / Q000502:physiology; D064092:Calbindin 1; D064026:Calbindins; D002118:Calcium / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D005013:Ethosuximide / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology*; D017874:Immediate-Early Proteins; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D019599:Mossy Fibers, Hippocampal / Q000737:chemistry / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000648:ultrastructure; D010320:Parvalbumins / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012032:Refractory Period, Electrophysiological / Q000502:physiology; D064030:S100 Calcium Binding Protein G / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics
D000927:Anticonvulsants; C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D064030:S100 Calcium Binding Protein G; D014157:Transcription Factors; D005013:Ethosuximide; D002118:Calcium