Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses.
Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.
Abramov
Efrat
E
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dolev
Iftach
I
Fogel
Hilla
H
Ciccotosto
Giuseppe D
GD
Ruff
Eyal
E
Slutsky
Inna
I
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D015260:Neprilysin / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D011480:Protease Inhibitors; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D015244:Thiorphan; D015260:Neprilysin