The ephemeral lives of synaptic vesicles

So I already talked about how muscles are insane and you would never believe that they can work as fast as they do once you see how they work.  This is even truer of your brain.

We all (hopefully) know that your brain is filled with cells called neurons and that the things you call thoughts are really electrical impulses traveling among those neurons.  Good. 

So for now I’m going to leave aside just how that electrical impulse travels through a single neuron, because while that is cool and also mind-boggling in its speed-despite-complexity, it doesn’t make for a very interesting blog post (well, I think it does, but that’s me and not everyone else in the universe).  What does make for a marginally more interesting blog post is what happens between neurons – how that signal hops from one neuron to the next.

Here’s why it’s more interesting.  While a signal traveling within a neuron is essentially an electrical signal, propagating quickly like any electrical signal would (you know, like in a copper wire or something), the transmission that goes on between neurons is chemical.  There’s a very small space between the end of one neuron and the start of the next, and this space is called a ‘synapse’.  And somehow the signal from the first neuron has to jump across that space and start a new electrical signal in the next neuron. 

The neuron accomplishes this by releasing little packets of chemicals (aptly named neurotransmitters) that make their way across the synapse and bind onto the surface of the next neuron, catalyzing a whole cascade of crazy events and eventually (possibly and with all standard biological “nothing works exactly the way I say it does” caveats) resulting in the instigation of another electrical signal in the next neuron.

Quickly, some terminology.  And I made some pretty pictures to show it to you!  

Like I already said, the space between neurons is the synapse.  The first neuron is the presynaptic neuron, which has a very long fiber called an axon, which has an end called an axon terminal.  The second neuron is the postsynaptic neuron (which also has its own axon, but that’s not important right now).  

The chemical being transmitted is a neurotransmitter.  (There are many kinds of neurotransmitter, and you’ve probably heard of a few of them: dopamine and serotonin and adrenaline and the like.  Ironically, none of these are the standard neurotransmitter – used by 9 out of every 10 neurons – which is glutamate.  Have you even heard of glutamate?  I didn’t think so.  Poor glutamate...)  The ‘packets’  I mentioned earlier are really called vesicles, and they’re bubbles made of cell membrane.  I’ll define other new terms as I go.

Okay, this is taking way too long already.  I need to get to the point.

In case you get bored before you reach the end of this post, the point is this: vesicle recycling is awe-inspiring. 

So before the electrical signal reaches the terminal, here is what is already in place in the presynaptic axon terminal.  There are a whole bunch of “docked” vesicles, full of glutamate, already lined up (docked) along the synapse.  There are a lot of closed calcium channels sitting right next to those vesicles.  There is also a whole host of other vesicles waiting in a pool right behind the docked vesicles.  Okay.

Docked vesicle with a green calcium channel next to it

When the electrical signal reaches the axon terminal, the change in voltage opens the calcium channels, which let a lot of calcium into the terminal.  This calcium binds onto some proteins called SNAREs which are holding the docked vesicles in place.  That binding causes the SNAREs to torque and shove the vesicle into the cell membrane, and they fuse with the cell membrane and spew their contents (glutamate) out into the synapse.  The glutamate floats over to the other side and starts a chain reaction in the postsynaptic neuron which is incredible but irrelevant to this story.

Before another signal can get propagated, new vesicles have to come and dock up against the calcium channels lining the synapse.  These vesicles come from the vesicle pool.  Now, because this is your brain and because neurons are firing like all the time, if this pool didn’t get replenished constantly your neurons would cease to function in a matter of moments.

I know.  Whenever I realize things like this I start freaking out that this process which was going on perfectly fine my whole life without me knowing it is suddenly at dire risk of stopping just because I now know that without it I’d die.  I understand if you want to hyperventilate a little.  Nevertheless rest assured that nothing’s going to stop your neurons from doing this any time soon.

But here’s what has to happen in order for that pool to get replenished.

First, those vesicles that fused with the cell membrane and spewed their contents, they’re now fully fused and make up part of that membrane.  So to compensate, new vesicles have to come out of the cell membrane.

This is achieved using proteins called clathrin, which all link up together and start yanking on the membrane, surrounding a little blob of it and molding that blob into a clathrin-coated sphere. 

Then this other protein called dynein comes along and pinches off the last little bit of membrane, and you’re left with a ball of membrane that looks suspiciously like a vesicle (because it is).

Then the clathrin breaks up and that vesicle sits around looking silly with nothing in it.

To put something in it, you need some channels I neglected to mention, which are sitting in the membrane all the time just hanging out waiting to be taken up into a vesicle (this is kind of true and kind of not, but just go with it).  These channels are glutamate channels, and they sit in the membrane of the vesicle and pump glutamate into the vesicle.

It’s been too long since I took basic neurobiology to remember just how the channels know they’ve reached the ideal amount of glutamate in the vesicle, but take it from me – they know, and they stop pumping.  And there you have it, a nice shiny new vesicle waiting to enter the pool.

So let’s go through those many steps again and follow the Life Cycle of a Vesicle (the worst part is I’ve skipped a few steps for brevity so you’re going to see some previously unmentioned steps here!). 

First, here’s the picture.  Go ahead, admire it:

As usual, click to enlarge

You start with a neuronal membrane.  And suddenly, out of nowhere a little patch of membrane is encountered by clathrins (1).  And the clathrins start binding to each other and a chain reaction happens, and in a beautiful and miraculous turn of events a cute little sphere of membrane ends up caged in a soccer ball of clathrins (2–3).  And good old dynein comes along and cuts the cord (2), and the clathrins fall off (4), and behold, a brand-new empty vesicle!

This vesicle starts filling with glutamate (5), and when it reaches that Goldilocks-perfect concentration (6) it gets transported over to the pool to take its place at the back of the line (7).  It waits patiently while other older vesicles get pulled to the synapse ahead of it, and finally, finally it’s this loaded vesicle’s time to shine!  It gets transported straight to the membrane, where it is loosely tethered (8).  Then it is formally and properly docked (9).  Then it is ‘primed’, meaning it’s not only docked in the right place but it is dressed up all pretty for the ball and by God, it will be fused (10). 

Then the electrical signal comes (11).  Calcium floods into the terminal and binds to the proteins holding the primed vesicle.  The tortured proteins wrench violently, and the vesicle fuses and spills its guts like Snowden’s secret.  Thus ends the life of the vesicle, because it becomes One with the membrane and all its little parts go floating into the all-encompassing vastness of the cell and whatnot.  (Would you believe I’m still leaving out a few steps with this description?)

And now for the moment you’ve all been waiting for – this whole process, start to finish, happens on the order of milliseconds (ms).  Last I checked someone had calculated it at about twenty ms.  That’s twenty thousandths of a second. 

I mean wow, right?