Release probability · Grey Matter

Release probability is the chance that a spike arriving at a synapse makes a vesicle fuse and release its transmitter, and at most synapses in the brain it is well below one: a spike often releases nothing, which makes synaptic transmission noisy and adjustable at once.

Release probability. Release probability is the chance that a spike arriving at a synapse makes a vesicle fuse and release its transmitter, and at most synapses in the brain it is well below one: a spike often releases nothing, which makes synaptic transmission noisy and adjustable at once.

Each terminal holds its vesicles in functional pools. A few are docked and primed at the release site, the readily releasable pool, typically a handful per active zone and only 1 to 2 % of the vesicles in the terminal; a larger recycling pool (around 5 to 20 %) refills it during ordinary activity; and most of the rest form a reserve that is mobilised slowly, if at all. Whether a spike releases a vesicle depends on how many vesicles are primed and on how much calcium reaches each one, so the probability is a property of the synapse that changes from moment to moment.

At a typical cortical or hippocampal synapse a single spike releases zero or one vesicle, sometimes more (multivesicular release); measured average probabilities at low firing rates are around 0.1 to 0.3, with wide variation between synapses.

Where reliability matters, the brain uses many release sites in parallel. A motor nerve terminal has hundreds of active zones each with a low probability, and a single spike releases on the order of 20 to 60 vesicles at a human neuromuscular junction (more at larger animal junctions), enough to fire the muscle every time.

The probability is a control point. Short-term plasticity follows from it (a low probability leaves vesicles for later spikes, a high one depletes them), presynaptic receptors lower it by trimming calcium entry, and drugs such as those binding SV2A act on vesicle readiness.

A synapse is a gamble the brain can rig.

Unreliable single synapses add up to reliable circuits, and the odds of each one are the knob that plasticity, modulators and drugs turn.

Questions: How do endocannabinoids send a message backwards across a synapse? When a neuron is strongly depolarised, the calcium that enters it (or certain metabotropic receptors) activates enzymes in its membrane that make 2-AG, a lipid that is not stored but made on demand. 2-AG diffuses out of the cell, back across the cleft, and binds CB1 receptors on the presynaptic terminals that contact it. CB1 receptors inhibit the terminal's calcium channels, so the probability of release falls for tens of seconds, and with repeated activation the depression can become long-lasting. In depolarisation-induced suppression of inhibition, a pyramidal cell that fires hard uses this route to turn down the GABA arriving onto itself. How do GABA-B receptors on a terminal reduce the transmitter it releases? Presynaptic GABA-B receptors activate G proteins whose freed subunits bind the terminal's voltage-gated calcium channels and make them harder to open. Because release rises with roughly the fourth power of calcium entry, a modest cut in calcium lowers the probability of release substantially. On GABA terminals this is autoinhibition, limiting how much GABA the next spikes release; on glutamate terminals, as heteroreceptors, it lets nearby inhibition turn down excitation. Baclofen, a GABA-B agonist, uses this effect in the spinal cord to reduce spasticity. How many vesicles does a single spike release? At a typical synapse in the cortex or hippocampus, usually none or one: each release site has a probability of release of roughly 0.1 to 0.3 at low firing rates, and only sometimes do two or more vesicles go together. Reliability comes from numbers, since a neuron receives input through many such synapses at once. A motor nerve terminal is built the other way, with hundreds of release sites, and one spike releases tens of vesicles (about 20 to 60 at human neuromuscular junctions, more in larger muscles of other animals), enough to fire the muscle fibre every time. A range such as one to two hundred vesicles per spike mixes these two very different kinds of synapse. What are the vesicle pools, and what happens when the ready one runs out? A terminal's vesicles fall into three functional groups: a readily releasable pool docked and primed at the active zone (about 1 to 2 % of the total), a recycling pool that refills it during normal activity (about 5 to 20 %), and a reserve pool holding most of the rest, mobilised only by intense stimulation. During a fast train each spike spends some of the ready vesicles, and if refilling cannot keep up, later spikes release less, which is short-term depression. Recovery takes from hundreds of milliseconds to seconds, depending on how quickly vesicles are recycled and primed again. How large the ready pool is, and how fast it refills, sets how long a synapse can follow a high-frequency input.