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 Alzheimer'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 excitatory transmission following high-frequency stimulation were greater in transgenic mice expressing mutant PS1. Mutants had enhanced synaptic inhibition, which may be a compensatory change offsetting an abnormally sensitized plasticity of excitatory transmission. Increasing inhibitory transmission in mutant animals even more with a benzodiazepine reverted synaptic potentiation to the levels of controls. These results support the potential use of benzodiazepines in the treatment of familial Alzheimer's disease.

Zaman SH ，Parent A ，Laskey A ，Lee MK ，Borchelt DR ，Sisodia SS ，Malinow R ... -  《NEUROBIOLOGY OF DISEASE》

Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1.

Parent A ，Linden DJ ，Sisodia SS ，Borchelt DR ... -  《NEUROBIOLOGY OF DISEASE》

Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice.

Trinchese F ，Liu S ，Battaglia F ，Walter S ，Mathews PM ，Arancio O ... -  《ANNALS OF NEUROLOGY》

The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.

Wen PH ，Hof PR ，Chen X ，Gluck K ，Austin G ，Younkin SG ，Younkin LH ，DeGasperi R ，Gama Sosa MA ，Robakis NK ，Haroutunian V ，Elder GA ... -  《EXPERIMENTAL NEUROLOGY》

Functional phenotype in transgenic mice expressing mutant human presenilin-1.

Mutations in the presenilin-1 (PS1) gene cause approximately 50% of cases of early onset familial Alzheimer's disease. The function of this protein remains unknown. We have made an electrophysiological study of hippocampal slices from transgenic mice expressing either a normal human PS1 transgene (WT) or one of two human PS1 transgenes bearing pathogenic mutations at codon M146 (M146L and M146V). Medium and late afterhyperpolarizations in CA3 pyramidal cells were larger in mice expressing either mutant form compared with WT and nontransgenic controls. Calcium responses to depolarization were larger in M146L mice compared with nontransgenic littermates; synaptic potentiation of the CA3 to CA1 projection was also stronger. These results demonstrate disruption of the control of intracellular calcium and electrophysiological dysfunction in PS1 mutant mice.

Barrow PA ，Empson RM ，Gladwell SJ ，Anderson CM ，Killick R ，Yu X ，Jefferys JG ，Duff K ... -  《NEUROBIOLOGY OF DISEASE》