Mitochondria: Powerhouses of Presynaptic Plasticity

The question of how certain synapses maintain high frequency neurotransmission has long intrigued neuroscientists. The calyx of Held synapse fires at rapid frequencies to localize sound. In order to transmit a signal to the postsynaptic cell, the presynaptic terminal must have vesicles available to release neurotransmitter. To continue firing, it must control the supply of vesicles in order to sustain a prolonged period of demand.

Calcium levels are an important regulator of vesicle dynamics. Large presynaptic calcium currents reduce vesicle release probability after successive pulses, while smaller currents result in facilitation. There are likely many types of vesicle pools with different release kinetics and sensitivities to calcium. Vesicles that are slower to release rely on a buildup of residual calcium to activate; buffering presynaptic calcium levels with calcium chelators prevents their release and therefore prevents facilitation (Sakaba & Neher, 2001). Presynaptic calcium levels must be carefully regulated in terms of concentration and timing, to optimize vesicle release kinetics for sustained high frequency activity. Regulation is performed not only by calcium channels, but by organelles like mitochondria that re-release calcium during the intervals between action potentials or after stimulation has ceased.

Mitochondria are a key part of the synaptic architecture in the calyx of Held. Here, mitochondria are tethered to the presynaptic membrane by filaments and form mitochondria-associated adherens complexes (MACs) with presynaptic membranes. The mitochondria that form these complexes are more structurally complex than other mitochondria; in their intimate proximity to synapses (Rowland et al., 2000) they play a key role in calcium buffering and vesicle cycling (Billups & Forsythe, 2002) as well as in vectored ATP release, wherein mitochondria produce ATP targeted to sites of vesicle release, fueling synaptic activity (Perkins et al., 2010).

In this issue of The Journal of Physiology, Yang and colleagues further investigate the role of mitochondria in short term facilitation and augmentation. They show that a specific inhibitor of the mitochondrial sodium/calcium exchanger (mNCX) reduces short term facilitation, suggesting that mitochondrial calcium release (MCR) during the interval between action potentials plays a role in sustaining neurotransmitter release during high frequency stimulation. MCR occurs in mature calyces in which cytosolic calcium is low due to more developed calcium clearance mechanisms (Yang et al., n.d.).

As calyces mature, they form swellings, which contain synaptic junctions (Rowland et al., 2000). The authors hypothesize that the maturity-onset contribution of MCR to high frequency stimulation is due in part to the development of these swellings and the close approximation of mitochondria to active zones. Even upon reaching maturity, there is structural heterogeneity among calyces of Held: calyces with swellings undergo short term facilitation and reduced depression and are less likely to experience action potential failure (Grande & Wang, 2011). Much larger than other synapses in the central nervous system, the calyx of Held lends itself particularly well to both electrophysiology and imaging techniques. Future studies should capitalize on this by exploring the structural underpinnings of Yang et al.’s findings.

Yang et al. further determined that the mNCX inhibitor reduced vesicle release probability of the fast releasing vesicle pool in conditions of low external calcium, suggesting that the facilitation promoted by MCR is linked to increased vesicle release probability. The mNCX thus functions as a separate source of residual calcium displaced from the active zone that may encourage reluctant vesicles to enter the fast releasing pool. MCR may also activate changes in the rich actin structure of the calyceal presynaptic terminal that influence vesicle cycling between pools (Lee et al., 2012) (Figure 1). Yang et al.’s findings raise the intriguing possibility that vesicles situated close to the mitochondria experience a privileged calcium source that primes them for participation in the fast releasing pool.

Figure 1.

Illustration of a presynaptic terminal with a mitochondrion localized near the membrane. The mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) releases calcium targeted to the membrane. The mitochondrion is associated with actin filaments which link vesicles to one another. During high frequency stimulation, the residual calcium supplied by the mNCX facilitates the recruitment of reluctant vesicles to supply the fast releasing pool.