#11100 NTR: Synaptic Vesicle Pools

[Paul Denny]

In PMID_22745285, an excellent recent review, authors discuss at least three functional classes of Synaptic Vesicle - labelled as "Pools" and usually called
1) readily releasable pool (RRP)
2) recycling pool
3) resting pool
As of 2012 (and, I think, right now), There were / are no widely agreed molecular tags distinguishing these pools, yet these terms and the relative size (sometimes defined as the number of vesicles) of each pool is frequently used in the literature.
I'd like to be able to have GO terms created for these types of vesicle.
However, Although this appears to be a request for a cellular component term, the functional outcome of differences in the sizes of the pools is ultimately a difference in the amount of vesicle fusion with the presynaptic membrane, pore formation and opening resulting in neurotransmitter release into the synaptic cleft.
So this is a cellular component involved in the process of neurotransmitter release. how can this fit into the GO?

[Paola Roncaglia]

Hi Paul,

I'm listing some suggestions for your new terms below, but I also have questions that I hope you may help me with, as I haven't had a chance to read the full paper yet. Here they go:

1) GO:NEW1 readily releasable pool
is_a cellular_component
has_part GO:0008021 synaptic vesicle
Definition: ...contains about 10 synaptic vesicles (corresponding to about 5% of the total number of synaptic vesicles at a resting terminal bouton)...??
PMID: 22745285, GOC:pad
exact synonym: RRP
exact synonym: readily releasable pool of synaptic vesicles

2) GO:NEW2 recycling pool
is_a cellular_component
has_part GO:0008021 synaptic vesicle
Definition: ...contains about 20 synaptic vesicles (corresponding to about 10% of the total number of synaptic vesicles at a resting terminal bouton)...??
PMID: 22745285, GOC:pad
exact synonym: recycling pool of synaptic vesicles

3) GO:NEW3 resting pool
is_a cellular_component
has_part GO:0008021 synaptic vesicle
Definition: ...contains about 170 synaptic vesicles (corresponding to about 85% of the total number of synaptic vesicles at a resting terminal bouton)...??
PMID: 22745285, GOC:pad
exact synonym: resting pool of synaptic vesicles

4) if needed:
GO:NEW4 total recycling pool
is_a cellular_component
has_part GO:NEW1 readily releasable pool
has_part GO:NEW2 recycling pool
Definition: A [cellular component term] made up of GO:NEW1 and GO:NEW2 [depending on their final names].
PMID: 22745285, GOC:pad

Questions:

a) The primary names as suggested above sound a bit generic. I'd certainly add exact synonyms such as 'readily releasable pool of synaptic vesicles', but I'm wondering if the primary names should be e.g. 'synaptic vesicle readily releasable pool' - or would that sound like a part of a single vesicle? Any suggestions?

b) Can we think of any more specific parent(s) for these terms?
My suggestions:
- is_a GO:0044456 'synapse part' ('Any constituent part of a synapse, the junction between a nerve fiber of one neuron and another neuron or muscle fiber or glial cell.'); though we prefer 'part' terms not to be the only is_a parents, in general;
- part_of GO:0043195 'terminal bouton'? ('Terminal inflated portion of the axon, containing the specialized apparatus necessary to release neurotransmitters. The axon terminus is considered to be the whole region of thickening and the terminal bouton is a specialized region of it.')

c) Paul, could you please add to the definitions, especially to specify what differentiates the pools in terms of fast/slow/neurotransmitter release etc. To this regard, I noticed that the abstract says: "Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity." So what may be relevant to neurotransmitter release may actually be the regulation of vesicle pool... size? type?
This ties in with your question: "So this is a cellular component involved in the process of neurotransmitter release. How can this fit into the GO?". For CC terms describing protein complexes, we sometimes use the relationship 'capable_of_part_of [insert biological process here]. Depending on your specification of what differentiates the pool terms here, we might evaluate the possibility of adding 'capable_of_part_of' here too - we've never done it other than for protein complexes but it could be a possibility.

d) is GO:NEW4 needed?

Thanks,
Paola
P.S. In the ontology SF request interface, we usually reserve the 'label' field to indicate the type of request, rather than the submitter; that helps with sorting and summarizing requests. We can also sort requests by submitter ('Creator'), so initials are really best placed within the request itself :-) Thanks!

[Paul Denny]

11100 NTR: Synaptic Vesicle Pools

Hi Paola
thanks for this - I think part_of GO:0043195 'terminal bouton' is best as parent.

Another good review is PMID: 15611727 - but confusingly, uses slightly different nomenclature!

In the definitions, I think it would be best not to specify numbers of vesicles, because numbers vary between synapses in different species and also between different synapses in different anatomical locations, e.g. hippocampus versus other brain regions. Pool sizes (and hence numbers of vesicles) also seem to scale with size of the active zone at the synapse. I think simply percentages better so e.g.

1) GO:synaptic vesicle, readily releasable pool
is_a cellular_component
has_part GO:0008021 synaptic vesicle
Definition: are the first vesicles to be released as a result of chemical or electrical stimulation e.g. by an action potential, have the highest presynaptic membrane fusion probability and correspond to about 1% of the total number of synaptic vesicles at a resting terminal bouton.
PMID: 22745285, GOC:pad
exact synonym: RRP
exact synonym: readily releasable pool of synaptic vesicles

Standard assay for the size of the RRP is an osmotic challenge, typically application of normal saline made hypertonic by the addition of 500 mOsm/L sucrose - this is independent of electrical stimulation (action potentials) and also doesn’t require calcium - it’s non-physiological, but used extensively in the field.

Difficult to define the recycling pool as it is often referred to as the difference between the number of vesicles in the Total recycling pool and the number in the readily releasable pool!

2) GO:synaptic vesicle, recycling pool
is_a cellular_component
has_part GO:0008021 synaptic vesicle
Definition: vesicles that repopulate vacancies within the readily releasable pool and require more significant stimuli in order to release neurotransmitter; contains about 10-15% of the total number of synaptic vesicles at a resting terminal bouton.
PMID: 22745285, GOC:pad
exact synonym: recycling pool of synaptic vesicles

3) GO:synaptic vesicle, resting pool
is_a cellular_component
has_part GO:0008021 synaptic vesicle
Definition: a set of vesicles that remain unreleased even after prolonged stimulation that causes a saturating degree of vesicular turnover; contains about 50-80% of the total number of synaptic vesicles at a resting terminal bouton.
PMID: 22745285, GOC:pad
exact synonym: resting pool of synaptic vesicles

Yes, I think regulation of the sizes of the different pools - usually believed to be due to regulating the NUMBER of vesicles in a pool is most important for regulating neurotransmitter release.

I don’t think we need to the fourth term, BUT, one complication is that there is evidence for a “super-pool” of vesicles that encompasses (some?) vesicles belonging to both recycling and resting pools (see “Vesicle Superpool and Interterminal Exchange” on p12 of PMID:22745285) these are vesicles that are trafficked between boutons. I don’t want to go into this concept just yet, until the researchers reach more consensus.

Not sure about using 'capable_of_part_of' - I guess vesicles are a similar to an enormous protein complex, but really, are much more than that since they have a membrane structure - they’re really more like a mini-organelle.

[Paola Roncaglia]

Thanks Paul. Here are the terms, with only minimal variation from your suggestions:

[Term]
id: GO:1990474
name: synaptic vesicle, readily releasable pool
namespace: cellular_component
def: "A pool of synaptic vesicles that are the first to be released as a result of chemical or electrical stimulation e.g. by an action potential, have the highest presynaptic membrane fusion probability and correspond to about 1% of the total number of synaptic vesicles at a resting terminal bouton." [GOC:pad, PMID:22745285]
synonym: "readily releasable pool of synaptic vesicles" EXACT []
synonym: "RRP" RELATED []
is_a: GO:0033267 {is_inferred="true"} ! axon part
is_a: GO:0044456 {is_inferred="true"} ! synapse part
relationship: has_part GO:0008021 ! synaptic vesicle
relationship: part_of GO:0043195 ! terminal bouton

[Term]
id: GO:1990475
name: synaptic vesicle, recycling pool
namespace: cellular_component
def: "A pool of synaptic vesicles that repopulate vacancies within the readily releasable pool (RRP) of synaptic vesicles, and require more significant stimuli than the RRP in order to release neurotransmitter; contains about 10-15% of the total number of synaptic vesicles at a resting terminal bouton." [GOC:pad, PMID:22745285]
synonym: "recycling pool of synaptic vesicles" EXACT []
is_a: GO:0033267 {is_inferred="true"} ! axon part
is_a: GO:0044456 {is_inferred="true"} ! synapse part
relationship: has_part GO:0008021 ! synaptic vesicle
relationship: part_of GO:0043195 ! terminal bouton

[Term]
id: GO:1990476
name: synaptic vesicle, resting pool
namespace: cellular_component
def: "A pool of synaptic vesicles that remain unreleased even after prolonged stimulation that causes a saturating degree of vesicular turnover; contains about 50-80% of the total number of synaptic vesicles at a resting terminal bouton." [GOC:pad, PMID:22745285]
synonym: "resting pool of synaptic vesicles" EXACT []
is_a: GO:0033267 {is_inferred="true"} ! axon part
is_a: GO:0044456 {is_inferred="true"} ! synapse part
relationship: has_part GO:0008021 ! synaptic vesicle
relationship: part_of GO:0043195 ! terminal bouton

As for your note
"Yes, I think regulation of the sizes of the different pools - usually believed to be due to regulating the NUMBER of vesicles in a pool is most important for regulating neurotransmitter release."
there is an existing term for 'synaptic vesicle recycling' (that Becky created recently) that might be useful here ("The trafficking of synaptic vesicles from the pre-synaptic membrane so the vesicle can dock and prime for another round of exocytosis and neurotransmitter release. Recycling occurs after synaptic vesicle exocytosis, and is necessary to replenish presynaptic vesicle pools, sustain transmitter release and preserve the structural integrity of the presynaptic membrane."). If this is the case, you may request regulation terms via TermGenie. Otherwise, feel free to open a separate ontology request ticket with all the necessary details.

Closing now, but feel free to comment if you have any concern. Thanks!

Paola

[Paul Denny]

Thanks Paola - look good, but please would you add an EXACT synonym to

id: GO:1990476
name: synaptic vesicle, resting pool

of "reserve pool" (based on PMID:15611727)

Thanks Paul

[Paul Denny]

Sorry, meant this:

"reserve pool of synaptic vesicles"

[Paola Roncaglia]

Done.
Cheers
Paola