title: β-Amyloid inhibits E-S potentiation through suppression of cannabinoid receptor 1-dependent synaptic disinhibition.
abstract: It has been widely reported that β-amyloid peptide (Aβ) blocks long-term potentiation (LTP) of hippocampal synapses. Here, we show evidence that Aβ more potently blocks the potentiation of excitatory postsynaptic potential (EPSP)-spike coupling (E-S potentiation). This occurs, not by direct effect on excitatory synapses or postsynaptic neurons, but rather through an indirect mechanism: reduction of endocannabinoid-mediated peritetanic disinhibition. During high-frequency (tetanic) stimulation, somatic synaptic inhibition is suppressed by endocannabinoids. We find that Aβ prevents this endocannabinoid-mediated disinhibition, thus leaving synaptic inhibition more intact during tetanic stimulation. This intact inhibition opposes the normal depolarization of hippocampal pyramidal neurons that occurs during tetanus, thus opposing the induction of synaptic plasticity. Thus, a pathway through which Aβ can act to modulate neural activity is identified, relevant to learning and memory and how it may mediate aspects of the cognitive decline seen in Alzheimer's disease.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Orr
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Klotz
authors.affiliation: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wright
authors.affiliation: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.affiliation: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Seubert
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: madison@stanford.edu.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Madison
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D043884:Receptor, Cannabinoid, CB1; C075222:amyloid beta-protein (1-42)