Enhanced epileptogenic susceptibility in a genetic model of reactive synaptogenesis: the spastic Han-Wistar rat.
Our laboratory has been studying the spastic Han-Wistar (sHW) rat as a model of neuronal degeneration. Mutant sHW rats display a number of developmental abnormalities that eventually lead to hippocampal pyramidal cell death and synaptic reorganization starting around 30 days of age. The present study examined the contribution of hippocampal reorganization to the expression of seizures induced by systemic injections of kainic acid. Behavioral observations, EEG recordings and hippocampal Fos protein expression in these animals indicated that mutants develop paroxysmal discharges and seizures earlier than controls and the intensity of epileptic manifestations is greater. Kainate injections were lethal in 50% of mutants compared to only 5% of controls. Fos expression was increased approximately twofold in the mutant hippocampus, implicating abnormal excitation in this region. Additional studies in untreated animals indicated that GluR2 mRNA expression was significantly increased throughout the hippocampus in mutant animals, possibly contributing to the enhanced susceptibility to kainate treatment. These results confirm the role of synaptic reorganization in the increased propensity to develop epileptic discharges. Our data also underscore the usefulness of this natural model of cell degeneration and reactive synaptogenesis for understanding the mechanisms of neuronal hyperexcitability.
Cepeda
Carlos
C
Mental Retardation Research Center, University of California, Los Angeles, Calif 90095, USA. ccepada@mednet.ucla.edu
Crawford
Cynthia A
CA
Margulies
Jody E
JE
Watson
Joseph B
JB
Levine
Michael S
MS
Cohen
Randy W
RW
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011922:Rats, Mutant Strains; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics; D013569:Synapses / Q000378:metabolism / Q000473:pathology
D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid