Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death

AUTOR(ES)

Hernández-Sánchez, Catalina

FONTE

The National Academy of Sciences

RESUMO

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 IIα 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 [3H]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.

Documentos Relacionados

• Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1
• Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.
• Complete heart block and sudden death in mice overexpressing calreticulin
• Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice
• Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice