title: Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice.
abstract: Synaptic transmission was studied in hippocampal slices from aged (12-14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3-CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 microM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4+/-0.6 s; TAS10, 6.9+/-1.7 s). To study gamma-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 microM) and D-AP5 (50 microM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing.
authors.affiliation: Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, United Kingdom. jon.2.brown@gsk.com
authors.forename: Jon T
authors.initials: JT
authors.lastname: Brown
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D003344:Cortical Synchronization; D004195:Disease Models, Animal; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D026902:Potassium Channel Blockers; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D018691:Excitatory Amino Acid Antagonists; D026902:Potassium Channel Blockers; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D015761:4-Aminopyridine