Trends in Neurosciences
ReviewFacilitation, augmentation and potentiation at central synapses
Section snippets
Defining the binomial parameter P
Whether or not the Ca2+ that enters the nerve terminal during any one action potential (AP) releases a given fusion-competent vesicle2, 3, 4, 5, 6, 7, 8, 9, 10 (Box 1; Fig. 1) is dependent on several factors. These factors might not be identical at all contributory release sites, or even from AP to AP. Because repetitive release involves an often non-stationary population of all-or-none events, P is just as difficult to define in a precise and unambiguous way as n is (the number of points from
Factors that might influence P
The factor that determines the very different values of P (0.01 to 0.9) at different release sites could simply be a difference in local Ca2+-buffering or affinity, or both. At a ‘high P’ synapse, for example, some Ca2+-binding sites might already be occupied at rest, increasing affinity at other binding sites and reducing the requirement for additional Ca2+ to enter during an AP (Box 3). Alternatively, the AP might have different characteristics at different terminals, since the presynaptic Ca
Release probability varies dramatically from connection to connection
Release probability is rarely 1, even after significant periods of rest, and can vary widely. Estimates vary from <0.01 at specific pyramidal-cell to interneurone connections in the neocortex (see, for example, Ref. 22), to as high as 0.9 at the calyx of Held (Ref. 23) and at pyramidal inputs onto other classes of interneurones in CA1 (Ref. 24), with pyramidal-cell to pyramidal-cell connections being intermediate (0.3–0.6, 24, 25). Thus, at low frequencies, a release will either occur at every
Facilitation
Release correlates with both the steady-state [Ca2+]i and the size of the Ca2+ transient33. If one or more of the proposed four Ca2+ binding sites associated with the release machinery is already occupied, a Ca2+ transient that is subthreshold when no sites are occupied, might now reach release threshold (Fig. 2). Moreover, occupation of one binding site increases the affinity at others and Ca2+ cooperativity declines with facilitation, which suggests prior occupation of some Ca2+ binding sites
Augmentation
Augmentation is also Ca2+ dependent: presynaptic injection of EGTA (a Ca2+ chelator) prevents augmentation without affecting low-frequency release, or synaptic depression (squid giant synapse43). However, augmentation decays more slowly than facilitation (τdecay, 7 s at the frog neuromuscular junction) and ‘each impulse adds an increment of potentiation and increases τdecay of potentiation’44. At strongly facilitating pyramidal cell to interneurone connections in the neocortex, augmentation is
When and where are facilitation and augmentation expressed functionally?
These facilitating or augmenting effects are not readily apparent if P is very high and most available release sites have become refractory after the first AP. However, if many events are recorded and those in which the postsynaptic event is unusually small are selected for analysis, facilitation of the second EPSP, even at very high P connections can be demonstrated24. Pyramidal cell to pyramidal cell connections are an intermediate example that typically exhibit depression, but are able to
The mechanisms underlying augmentation
With cooperative Ca2+ binding (Box 3), unbinding rates would change with occupation. Occupancy of a single site might decay within a few tens of milliseconds, whereas binding at a third site might decay more slowly. However, τdecay for augmentation continues to increase with spike number well beyond three APs. The decay of augmentation is proposed to represent removal of intraterminal Ca2+. It is slowed by Na+ accumulation (which slows Ca2+ extrusion by Na+–Ca2+ exchange) or by the binding of Ca
Potentiation
Potentiation (post-tetanic potentiation or PTP) is more slowly developing than facilitation or augmentation, and decays more slowly (τdecay tens of seconds to minutes, see, for example, 54, 55). It is thought to result from the Ca2+-dependent mobilization of the reserve pools of vesicles and requires relatively high-frequency or tetanic firing for sufficient Ca2+ loading of the terminals (Fig. 3). If mobilization of the reserve pool is indeed the mechanism, it suggests that a larger readily
A simple circuit with a role in pattern generation?
An example of alternating patterns of presynaptic firing in vivo is seen in the hippocampus during exploration, particularly of a novel environment. Periods of theta activity appear as oscillations in the EEG at a frequency of 5–12 Hz, which cease when exploration ceases. Pyramidal cells fire on the negative phase of the wave: some generate burst discharges, some produce single spikes and some do not contribute to the rhythm generated under those particular behavioural conditions. The timing
Uncited reference
Ref. 36
Acknowledgements
The work from the author’s laboratory referred to in this article was supported by the Medical Research Council and Novartis Pharma (Basel). The author thanks R. Llinás, E. Stanley and T. Sihra for their advice in the preparation of this article.
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