Background

A central theme of the lab has been to study the physiology of endbulb synapses. The framework we use to understand synaptic physiology was developed by Bernard Katz and colleagues.

Each endbulb is composed of a large number of release sites. Each release site maintains a pool of vesicles that contain neurotransmitter. Some of these vesicles occupy a special place in the release site: they are docked to the inside of the presynaptic membrane, and are primed to release their contents into the synaptic cleft when the action potential arrives. These vesicles make up the readily releasable pool.

Electron micrograph of an endbulb (blue) and bushy cell (red). The endbulb has many small vesicles filled with neurotransmitter and two large mitochondria. There is one release site in this cross-section towards the right of the endbulb. From Ngodup et al. (2015).

When an action potential arrives, it triggers the opening of calcium channels, and calcium flows into the presynaptic terminal. The calcium binds to sensors on the vesicle that drive fusion of the vesicle and presynaptic membranes. Not all the vesicles fuse, however, and it appears that this is a fundamentally random process. The likelihood that a vesicle fuses is called the probability of release.

A surprisingly good analogy to this is a package of Halloween M&M‘s. You can think of all the M&M‘s in the package as the readily releasable pool. This is how many vesicles the synapse has to work with. But only some of them are any given colour, say green. You can think of the green M&M‘s as the vesicles that get released in response to an action potential. Each package has about the same number of M&M‘s, but the number of green ones varies a lot. In fact, it follows a binomial random distribution. This is true in neurotransmitter release too. Each time an action potential triggers neurotransmitter release, the actual number of vesicles that fuses varies randomly. Those vesicles get used up and need to be replenished. This doesn‘t happen with M&M‘s, of course. If you eat the green ones, they don‘t come back.

When a vesicle fuses, the neurotransmitter inside is released and binds to receptors on the postsynaptic cell and activates them. At the endbulb, the neurotransmitter is glutamate, and the receptors are of two types, AMPA receptors and NMDA receptors. When those receptors are activated, they cause positive current to flow into the cell. The amount of current caused by a single vesicle is called the quantal size. Individual vesicles release spontaneously all the time, so quantal size is easy to measure. These are called miniature postsynaptic currents or “minis”.

We study the causes and consequences of these three factors.

Spontaneous quanta released recorded in a bushy cell, in voltage clamp. Adapted from Chanda & X-F (2010).