title: The role of γ-secretase in hippocampal synaptic transmission and activity-dependent synaptic plasticity.
abstract: γ-Secretase plays an important role in the generation of amyloid beta and the activation of Notch receptors. In the hope that the reduction of amyloid production can help to battle Alzheimer's disease (AD) secretases were suggested to represent a potential therapeutic targets. However, the role of γ-secretase in cellular mechanisms of memory formation under physiological conditions remained to be clarified. To this end, γ-secretase was inhibited by bath-application of DAPT or Compound E and the effects on activity-dependent hippocampal synaptic plasticity and basal synaptic transmission in acute hippocampal slices from Wistar rats were examined. Bath application of DAPT or Compound E over the whole recording period of field excitatory postsynaptic potential (fEPSP) caused a reduction of synaptic potentiation within 1h after 3×1s 100Hz/10min stimulation (HFS) of Schaffer-collateral CA1 synapses. Notably, DAPT and Compound E inhibited effectively long-term potentiation (LTP) of fEPSPs when it was applied after HFS, but not if applied only during the tetanization paradigm. Compounds did not affect basal synaptic transmission, paired-pulse facilitation and NMDA mediated fEPSPs. Our data thus imply that γ-secretase plays a role in LTP and most notably for the persistence of activity dependent synaptic plasticity, presumably through the reduction of endogenous amyloid beta and/or Notch receptor activation. Targeting of γ-secretase to prevent the onset of AD might by itself alter memory formation.
authors.affiliation: Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 138 YiXueYuan Road, Shanghai 200032, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Behnisch
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D017208:Rats, Wistar; D009435:Synaptic Transmission
chemical_list: C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; DAPT; Long-term potentiation (LTP); Synaptic transmission and plasticity; γ-Secretase