Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death.
The ability of the sulfonylurea receptor (SUR) 1 to suppress seizures and excitotoxic neuron damage was assessed in mice transgenically overexpressing this receptor. Fertilized eggs from FVB mice were injected with a construct containing SUR cDNA and a calcium-calmodulin kinase IIalpha promoter. The resulting mice showed normal gross anatomy, brain morphology and histology, and locomotor and cognitive behavior. However, they overexpressed the SUR1 transgene, yielding a 9- to 12-fold increase in the density of [(3)H]glibenclamide binding to the cortex, hippocampus, and striatum. These mice resisted kainic acid-induced seizures, showing a 36% decrease in average maximum seizure intensity and a 75% survival rate at a dose that killed 53% of the wild-type mice. Kainic acid-treated transgenic mice showed no significant loss of hippocampal pyramidal neurons or expression of heat shock protein 70, whereas wild-type mice lost 68-79% of pyramidal neurons in the CA1-3 subfields and expressed high levels of heat shock protein 70 after kainate administration. These results indicate that the transgenic overexpression of SUR1 alone in forebrain structures significantly protects mice from seizures and neuronal damage without interfering with locomotor or cognitive function.
Section on Molecular and Cellular Physiology, Clinical Endocrinology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
C
C
Hernández-Sánchez
A S
AS
Basile
I
I
Fedorova
H
H
Arima
B
B
Stannard
A M
AM
Fernandez
Y
Y
Ito
D
D
LeRoith
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D016923:Cell Death; D006224:Cricetinae; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D015870:Gene Expression; D007608:Kainic Acid / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D018690:Excitatory Amino Acid Agonists; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; D064233:Sulfonylurea Receptors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517671:Camk2a protein, mouse; D007608:Kainic Acid