When a neuron goes into depolarization block (e.g. due to very high extracellular potassium) does it continue to release neurotransmitters? Surely action potentials no longer propagate along the neuron, but intracellular calcium can go quite high during depolarization block. Would this cause it to release synaptic vesicles? During depolarization block is the axon depolarized as well? Would the cell dump its available synaptic vesicles or would it stop transmitting all together? If it matters, I'm thinking of a cortical pyramidal neuron during cortical spreading depolarization/depression. Thanks for your thoughts.
The consequence of “depolarization block” in in vivo neurons could be complicated. Our simulation could be an alternative explanation.
I agree with Nicolas, high extracellular potassium make the neuron more easily depolarized by any excitatory presinaptic input.
Dear Thomas,
Your question is a very good one and the answer depends on numerous highly complex factors.
1. The type of neuron and especially calcium channels enriched at presynaptic terminals. As you may know, voltage-gated calcium channels (currents) driving transmitter release undergo rapid inactivation (few hundred ms) under prolonged depolarization. So, you may have a persistent depolarization, but this does not necessarily mean increased influx of calcium over extended time period.
2. The type and amount of calcium buffering proteins expressed at nerve terminals. In inhibitory interneurons, for example, under normal conditions, depolarization induced activation of transmitter release is typically very rapid, and is curtailed by calcium buffering mechanisms. As a result, to induce transmitter release, these terminals need very high-amplitude spikes with massive rise of calcium, to overcome the buffering barriers and to drive the fusion reaction.
3. Much also depends on the calcium sensors operating at nerve terminals (i.e. synaptotagmin isoforms and other sensors) as they have widely variable sensitivity for calcium and binding kinetics.
4. If I remember correctly, the membrane potential during depolarization block remains within negative ranges (between -35 and -20 mV), which is by any means not enough to drive sufficient calcium influx to activate exocytosis. Having said that, this is good enough to unblock presynaptic NMDA receptors and activate Ca2+ influx. If there is sufficient extracellular glutamate, then one would expect increased exocytosis over some time period. Again, this will be only transient as NMDA receptors also inactivate.
There are also other more complex players in this game, which should be considered, to answer your question. Cutting the story short, the answer is conditional NO. More precisely, one would expect transient increase of exocytosis during the initial depolarization, which will be followed by a shut-down of exocytosis at nerve terminals in most synapses.
If you have any questions, feel free to contact for further discussions.
Best regards,
Saak
I would "second" Saak's comment above. As an example of "[w]ould the cell dump its available synaptic vesicles or would it stop transmitting all together?," this can be found at the first synapse in the retina. So, first instead of saying that the cell would "dump" its neurotransmitter (NT), we would say that the terminal depleted its stores of NT. This happens in photoreceptors (PR) because of the L-type Ca2+ channels within the synaptic terminal. They do not inactivate, so, if you depolarize the PR long enough, you can deplete almost all of the pool of vesicles within the terminal. This is a form of depression at these synapses. Anyway, this is just a non-canonical example that is useful (I think) for learning purposes.
Ted
I have been wondering the same thing. I have some preliminary evidence that it can from in vivo striatal measurements. High light (3mW+) D2 cell activation by ChR2 can cause depolarization block in these cells (I have seen this and others have described it to me as well). Lower light levels cause these cells to fire without depolarization block. During strong light, I saw that cells previously inhibited by D2 activation at lower light levels (putative ChR2 negative D1 cells) are still inhibited (awake mice). It is possible to imagine other mechanisms for this via additional disinhibitory->inhibitory connections... so slice measurements would be the best way to assess the true story.
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