Impairment of hippocampal gamma-frequency oscillations in vitro in mice overexpressing human amyloid precursor protein (APP).
Alzheimer's disease is associated with a dramatic decline in cognitive performance including hippocampal-dependent memory. We have investigated one feature of hippocampal activity related to memory, the gamma (30-80 Hz)-frequency rhythm. Hippocampal slices from mice overexpressing the human amyloid precursor protein (APP)(SWE) mutation (TAS10) were compared at 8 and 16 months of age with wild-type littermates. In slices obtained from TAS10 mice aged 8 months the gamma-frequency activity evoked with bath application of 200 nm kainate was significantly (P < 0.05; n = 8 slices, five animals) impaired (area power, 5956 +/- 2487 microV(2)) compared to slices from wild-type animals (area power, 18 256 +/- 7880 microV(2)). At 16 months of age there was no longer a significant difference (P > 0.05; n = 11 slices from five animals) between slices from TAS10 and wild-type control mice as the wild-type mice now exhibited a marked age-dependent reduction in gamma-frequency activity (TAS10 area power, 5751 +/- 1573 microV(2); wild-type area power = 5379 +/- 1454 microV(2)). Although no dense-core plaques were evident at 8 months there was detectable amyloid labelling in the TAS10 mice which might account for the deficits in gamma activity observed at this age. Dense plaques were clearly evident in the TAS10, but not wild-type, mice at 16 months of age but no further reductions in gamma-frequency activity were seen in the TAS10 mice. These data suggest that deficits in network function in Alzheimer's disease occur early and are not directly correlated to amyloid load.
Driver
Joanne E
JE
School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JP, UK.
Racca
Claudia
C
Cunningham
Mark O
MO
Towers
Stephen K
SK
Davies
Ceri H
CH
Whittington
Miles A
MA
LeBeau
Fiona E N
FE
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics*; D001930:Brain Injuries / Q000235:genetics / Q000473:pathology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D013057:Spectrum Analysis
D016564:Amyloid beta-Protein Precursor; D002120:Calcium Channel Agonists; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D007608:Kainic Acid