Ca2+-dependent mechanisms of presynaptic control at central synapses

Abstract

Classically, a high-power association relates the neurotransmitter release probability to the concentration of presynaptic Ca2+. Activated by the action potential waveform, voltage-gated Ca2+ channels mediate Ca2+entry into presynaptic terminals. Inside the terminal, Ca2+ ions rapidly bind to endogenous intracellular buffers and could trigger Ca2+ release from internal Ca2+ stores. The resulting space-time profile of free Ca2+ determines the time course and probability of neurotransmitter release through the interaction with molecular release triggers strategically located in the vicinity of release sites. Following a rapid concentration transient, excess Ca2+ has to be removed from the cytosol through the process involving Ca2+ uptake by the endoplasmatic reticulum stores, sequestration by mitochondria, and/or extrusion into the extracellular medium. The ongoing synaptic activity could affect any of the multiple factors that shape presynaptic Ca2+ dynamics, thus arbitrating use-dependent modification of the neurotransmitter release probability. Here we present an overview of major players involved in Ca2+-dependent presynaptic regulation of neurotransmitter release and discuss the relationships arising between their actions.

Figure 1

A diagram of the presynaptic terminal depicting cellular mechanisms which contribute to the dynamics of free Ca²⁺. Cellular devices are labeled by green callouts, dynamic processes are shown in yellow callouts, and block arrows indicate the direction of action.

Figure 2

Presynaptic modulation by metabotropic glutamate receptors varies among axonal varicosities supplied by the same axon. (Modified from (Rusakov and others 2004)). A, A low-magnification fluorescence image of an area CA1 hippocampal interneuron (fragment) held in whole-cell mode. Acute slice, two-photon excitation (λ_x = 810 nm; Alexa Fluo 594 emission channel). Dendrite and axons are clearly distinguishable, as indicated. Scale bar, 10 μm. B, A high-magnification fluorescence image of an axon fragment from cell depicted in A. Two varicosities are shown (denoted 1 and 2; Alexa emission channel; increased brightness in the middle of varicosity 1 implies that its size in the Z direction exceeds the axon diameter 2-3-fold). Dotted arrow, line-scan positioning. Scale bar, 2 μm. C, Line-scan images (Ca²⁺-sensitive Fluo-4 emission channel) of the axon fragment shown in B in response to a pair of evoked action potentials (escape action currents, shown in upper traces). Left panel, control recording; right panel, 20 min following application of group III mGluR agonist L-AP4 (50 μM; average of 10 line-scans). D, Digitized traces of line-scan images in C, as indicated. Black line, control recording; red line, L-AP4 application. No effect of L-AP4 is seen in varicosity 1 whereas it is substantial in varicosity 2.

Figure 3

A diagram illustrating the dynamic range - time domain relationship for major cellular mechanisms that shape the dynamics of presynaptic Ca²⁺. The abscissa indicates relative contribution in terms of the affected concentration range of free intra-terminal Ca²⁺ in response to a single AP (A) and repetitive APs (B).