Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine

Mutations in presenilin 1(PS1) are the most common causes of familial Alzhe imer's disease (FAD). We examined synaptic physiology in hippocampal brain slices of transgenic mice expressing the FAD-linked PS1 deletion of exon 9 variant. Basal excitatory transmission and paired-pulse facilitation in PS1 mutant mice were unchanged. Short- and long-term potentiation of excitator y transmission following high-frequency stimulation were greater in transge nic mice expressing mutant PS1. Mutants had enhanced synaptic inhibition, w hich may be a compensatory change offsetting an abnormally sensitized plast icity of excitatory transmission. Increasing inhibitory transmission in mut ant animals even more with a benzodiazepine reverted synaptic potentiation to the levels of controls. These results support the potential use of benzo diazepines in the treatment of familial Alzheimer's disease. (C) 2000 Acade mic Press.