Figure 14: Scheme of the presynaptic transmission process. (A) In the resting state, the synaptic vesicles containing neurotransmitters (red circles) are localized near the synaptic membrane at the nerve terminal. (B)The arriving action potential produces an influx of calcium ions (green triangles) through voltage-gated calcium channels, leading to brief, high concentration gradients of intracellular free calcium ions ([Ca2+]i) (Catterall [119]). [Ca2+]i bind to the membrane of the synaptic vesicles, allowing them to fuse with the presynaptic membrane and then release neurotransmitters into the synaptic cleft (Almers and Tse [115]). (C) “Empty” synaptic vesicles undergo endocytosis, recycle, and refilling of neurotransmitters (Südhof [136]). The gradients of [Ca2+]i rapidly dissipate by diffusion and binding to intracellular calcium buffers as well as to the calcium-ATPase pump, and are eventually removed from the nerve terminal (Bennett et al. [116]). (D) When two closely timed (within several tens milliseconds) action potentials reach the nerve terminal, influxed [Ca2+]i due to the 2nd action potential sums up with [Ca2+]i which were triggered by the 1st action potential and stay locally for a short while (= residual [Ca2+]i). As a consequence, the 2nd action potential, when compared to the 1st action potential, yield a higher release probability of neurotransmitters (Katz and Miledi [124]; Malenka et al. [127]) leading to “paired-pulse facilitation” of synaptic transmission. (E) A bout of action potentials accelerates the release of neurotransmitters whereas the refilling of empty vesicles remains stagnant. Accordingly, the pool size of readily releasable vesicles gradually declines with a progression of the incoming signals, resulting in “frequency-dependent depression” of synaptic transmission (von Gersdorff and Matthews [121]).