Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC.

The contribution of intersynaptic transmitter diffusion to the AMPA receptor EPSC time course was studied in cultured CA1 hippocampal neurons. Reducing release probability 20-fold with cadmium did not affect the time course of the averaged AMPA receptor EPSC, even when receptor desensitization was blocked by cyclothiazide, suggesting that individual synapses contribute independently to the AMPA receptor-mediated EPSC. Deconvolution of the averaged miniature EPSC from the evoked EPSC showed that release probability decays only slightly faster than the EPSC, suggesting that the AMPA receptor EPSC time course is determined primarily by the asynchrony of vesicle release. Further experiments demonstrated that cyclothiazide, previously thought to affect only AMPA receptor kinetics, also enhances synaptic release.