Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, LONG-TERM POTENTIATION, PHYSIOLOGICAL FUNCTIONS, PRESYNAPTIC INHIBITION, RECEPTOR ANTAGONIST, MOLECULAR-STRUCTURE, NEURONAL-ACTIVITY, MICE LACKING, APPS-ALPHA, REVEALS, RELEASE, Amino Acid Sequence, Amyloid beta-Protein Precursor, Animals, Cells, Cultured, HEK293 Cells, Hippocampus, Humans, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Neurons, Peptides, Protein Binding, Protein Domains, Proteomics, Receptors, GABA-A, Synapses, Synaptic Transmission, Synaptic Vesicles, G065415N#53227840, General Science & Technology

Abstract:

Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer's disease, yet its physiological function remains unresolved. Accumulating evidence suggests that APP has a synaptic function mediated by an unidentified receptor for the shed APP ectodomain (sAPP). Here, we showed that the sAPP extension domain directly bound the sushi 1 domain specific to the gamma-aminobutyric acid type B receptor subunit 1a (GABABR1a). sAPP-GABABR1a binding suppressed synaptic transmission and enhanced short-term facilitation in hippocampal synapses via inhibition of synaptic vesicle release. A 17 amino acid peptide corresponding to the GABABR1a binding region within APP suppressed spontaneous neuronal activity in vivo. Our findings identify GABABR1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABABR1a function to modulate synaptic transmission.