Three major mechanisms has been proposed for astrocytic release: reversed operation of transporters, channels (see yYuriy's answer) and vesicular relase. Vesicular release is proposed for glutamate, D-serine, ATP and rather mysterious. Release through Best-1 is suggested only by a single group. Reversed transporter operation seem to be the case for GABA release. This sounds quite reasonable. Na+ accomulates during glutamate uptake and can reach the level for reverasal of GABA or glycine transporters.

Another interesting point that actocytes are non-excitble cells. So they do not generate action potentials. This however does not exclude that they can undergo quite significal local voltage changes. These voltage fluctuations may also reverse electrogenic transport.

Finally, one has to separate findings on release of gliotransmitters in cultured astrocytes and in astrocytes in slices or in vivo. Cultured astrocytes are known to generate many phenomena that do not exist in vivo. One famous example are calcium waves propogating through many cells in cultures. In slices or in vivo calcium activity does not seem to propogate this way.

It is very interesting question, but answer is yet to be found. Currently, even basic mechanisms of gliotransmitter release are debated. It is possible that some of them, such as ATP and glutamate, can be released both by exocytosis and non-vesicular pathways (connexinns or Best-1 channels), depending on physiological context or signals, astrocytes are receiving. The prevalence of one or another pathway can differ among brain regions or even with a region.

Good question, perhaps it is linked to the place where the calcium wave is initiated?..This is just speculation on my part.

Three major mechanisms has been proposed for astrocytic release: reversed operation of transporters, channels (see yYuriy's answer) and vesicular relase. Vesicular release is proposed for glutamate, D-serine, ATP and rather mysterious. Release through Best-1 is suggested only by a single group. Reversed transporter operation seem to be the case for GABA release. This sounds quite reasonable. Na+ accomulates during glutamate uptake and can reach the level for reverasal of GABA or glycine transporters.

Another interesting point that actocytes are non-excitble cells. So they do not generate action potentials. This however does not exclude that they can undergo quite significal local voltage changes. These voltage fluctuations may also reverse electrogenic transport.

Finally, one has to separate findings on release of gliotransmitters in cultured astrocytes and in astrocytes in slices or in vivo. Cultured astrocytes are known to generate many phenomena that do not exist in vivo. One famous example are calcium waves propogating through many cells in cultures. In slices or in vivo calcium activity does not seem to propogate this way.

My dears

Thanks for your good answers. I have a new idea which i'm working on it. I think maybe two key properties of Ca oscillation be involved in this problem:

first : the level of the Ca oscillation

second : time of Ca oscillation or in the other words "frequency'.

If any one is interested to this topic I would welcome him or her to write a paper about this topic and propose a new idea in this field.

I do agree with Alexey . Although transmitter release by astrocytes are now well accepted, their mechanisms and their impact on synaptic transmission are still under debate, not to say controversy. Cultures astrocytes seem to strongly differ to in vivo astrocytes which is not surprising. It was the same problem with synaptic transmission 15 years ago. While cultures astrocytes express "synaptic" vesicles, they are very rare in astrocytes in vivo. It may be that cellular interactions within a brain put a strong constraint on cellular biology of astrocytes.

Dear my friends

this figure maybe is useful and support my idea.

I want to share one testable hypothesis with you. Let's imagine that there is no vesicular release of gliotransmitters triggered by astrocytic Ca2+ transients in vivo [someone would be really angry with me for such speculations]. Would then these Ca2+ transients trigger some other forms of gliotransmitter release? Probably. There is one interesting protein called NCX, or Na+/Ca2+ exchanger. When Ca2+ is elevated in the cytoplasm, NCX exchanges it for Na+ from extracellular space. This in turn produces elevation of intracellular Na+. I wonder if this Na+ elevation:

1. can substantially downregulate efficiency of Na+ dependent glutamate, glycine or GABA uptake

2. can even reverse their transport

This can be a form of neuron-glia interaction and can be tested in a simple mathematical model. Experimental testing is also possible, but is a bit more difficult.

Dear Alexey

that was nice comment. I think following papers may be useful.

http://cercor.oxfordjournals.org/content/23/5/1240.short

http://www.jneurosci.org/content/21/2/477.short

But I'm think we should focus on relationship between GABA and astrocyte Ca.

Reading papers is always useful, but one should be critical. Researchers often disagree with each other and publish contracitory things. Inexperienced reader of these papers you may get really confused.

The things are never that simple. Indeed, the increased intracellular Na+ concentration is important for Na+ electrochemical potential and transporter mechanism operation. However, other mechanisms should also be taken into account such as activation by Na+i of Na+-K+ ATPase with perisynaptic localization, resulting in activation of glucose transport and lactate shuttle (

(e.g.see Cereb. Cortex (2002) 12 (5): 515-525. doi: 10.1093/cercor/12.5.515). Lactate released is not only a substrate but also a gliotransmitter

(e.g. Nature Communications 5,Article number: 3284 doi:10.1038/ncomms4284). And, importantly, the cotransmission should also be considered as an important mechanism. Dependent on the stimulation parameters, unique combinations of transmitters/cotransmitters are released, producing unique combinations of effects on glia.

Dear Petia

Thanks a lot for your valuable comments. It seems that you are familiar with these mechanisms. In agreement with your answer I think that we should consider the effect of AQ4 channel which is modulated extra synaptic Na.

See (Aquaporin-4 water channels and synaptic plasticity in the hippocampus)

Dear Hassanpoor,

Indeed, the mechanism of participation of the glial AQ4 in LTP/LTD induction is a very interesting one. I read the article you mentioned and I found there that Trk receptors were involved. This motivated me to search whether ephrins may also be involved in similar neuro-glial interaction related to LTP. I found the following interesting article "Neuron-glia communication via EphA4/ephrinA3 modulates LTP through glial glutamate transport" So, the list of signals that glia may "understand" and which trigger different intracellular mechanisms and glial responses seems to be a long one.

Dear Kupenova

Thanks for your contribution. I think intracellular astrocyte Ca signaling is the key of this problem. But there are some different theories and all related mechanisms have remaind unknown yet.

(Calcium signalling in glial cells_1998)

(Calcium signaling and gliotransmission in normal vs. reactive astrocytes_2012)

Now let us know if there is any relationship between intracellular astrocitic Ca and AQ4 Chanel? I think we should focus on it too.

Dear Hossein,

I see that you are especially interested in AQ4 channel. So you are probably familiar with the following paper "Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema ".

Thanks very much. I didn't have that paper in my data base. I add it and I'm reading it. it seems that our puzzle is more clear than before. we should connect these separate parts together and cerate our hypothesis in these days.

See:

Kirischuk, S., Parpura, V., and Verkhratsky, A. (2012). Sodium dynamics: another key to astroglial excitability? Trends in neurosciences 35, 497-506.

Parpura, V., and Verkhratsky, A. (2012). Homeostatic function of astrocytes: Ca(2+) and Na(+) signalling. Translational neuroscience 3, 334-344.

Nedergaard, M., and Verkhratsky, A. (2012). Artifact versus reality--how astrocytes contribute to synaptic events. Glia 60, 1013-1023.

Reyes, R.C., Verkhratsky, A., and Parpura, V. (2013). TRPC1-mediated Ca2+ and Na+ signalling in astroglia: differential filtering of extracellular cations. Cell calcium 54, 120-125.

Dear professor Verkhratsky

Many thanks for your valuable suggestions