AbstractPresynaptic terminals have been little studied as sites of synaptic integration because of inaccessibility. Gi/o-mediated presynaptic inhibition is ubiquitous and either reduces release probability (Pr) by inhibiting Ca2+ entry or inhibits directly at SNARE complexes. At CA1-subicular presynapses, 5-HT1B and GABAB receptors colocalize. GABABRs inhibit Ca2+ entry, whereas 5-HT1BRs Ca2+-dependently target SNARE complexes. We demonstrate that GABABRs, alter Pr, but 5-HT1BRs reduce cleft glutamate concentrations allowing strong inhibition of AMPA-but not NMDA-receptor responses. Simulations of glutamate release and receptor binding demonstrates that experimental effects on release and low affinity antagonism are well-fit by reduced release rates. Train-dependent presynaptic Ca2+ accumulation forces frequency-dependent recovery of neurotransmission during 5-HT1BR activation, consistent with competition between Ca2+-synaptotagmin and Gβγ at SNARE complexes. Thus, stimulus trains in 5-HT unveil dynamic synaptic modulation and a sophisticated hippocampal output filter, that itself is modulated by colocalized GABABRs which alter presynaptic Ca2+ allowing complex presynaptic integration.
Synaptic integration of subquantal neurotransmission by co-localized G protein coupled receptors in presynaptic terminals
