BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization

Background: BACE1 is a key enzyme in the generation of the A beta peptide that plays a central role in the pathogenesis of Alzheimer's disease. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. Examination of BACE1(-/-)mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1(-/-)mice. Results: We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1(-/-)mice, occasionally including generalized tonic-clonic and absence seizures. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1(-/-)mice relative to BACE1(+/+) littermates, and causes excitotoxic cell death in a subset of BACE1(-/-)mice. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1(-/-)mice. Finally, examination of the expression and localization of the voltage-gated sodium channel alpha-subunit Na(v)1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility. Conclusions: Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity. This finding has implications for the development of safe therapeutic strategies for reducing A beta levels in Alzheimer's disease. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.