Gap junction function in the nervous system

  1. Pythagorean

    Pythagorean 4,576
    Gold Member

    In part branching off a discussion here, but also a discussion I've always been interested in having. I also want to take some time to answer the question in that thread:

    axo-axonic gap junctions in the hippocampus are thought to play a role in generating ultra-fast oscillations that have a unique "spikelet" shape that participates in some higher level functions [1]:

    Axo-axonic gap junctions are also capable of antidromic action potentials [2] which can give alternate routes of excitation and inhibition (a gap junction, of course, acts somewhat like an inhibitor with respect to the neuron at the higher potential).

    and address this comment:

    Firstly, I'd just like to point at that it's true that ephaptic coupling, but electrical coupling through gap junctions is not considered ephaptic coupling [3]. Ephaptic coupling is coupling through environment, such as local electric fields and local ion exchange with extracellular space, not direct gap junction coupling.

    The well known gap junctions role is synchronization [4], but they also pass molecular signaling molecules, leading one author to refer to them as the "rosetta stones" of biology (because they can integrate electrophysiological and metabolic communication) [5]. Electrical synapses are also found extensively coupling GABAergic interneurons in the cortex, and are thought to participate in coincidence detection across inhibitory signals [6]. They also appear to functionally segregate portions of network [7]. Experiments in C.elegan show that interfering with different kinds of gap junctions can lead to numerous different functional deficiencies (from constipation to chemotaxis to death) [8]. And of course, the nervous system is dominated by gap junctions in early development [9].

    The chief blockers and openers of gap junctions (because gap junctions can be open, rectifying, or closed) are carbenoxolone and trimethylamine.

    [1] http://www.sciencedirect.com/science/article/pii/S0361923003002302
    [2] http://www.sciencedirect.com/science/article/pii/S0306452298007556
    [3] http://www.nature.com/neuro/journal/v14/n2/abs/nn.2727.html
    [4] http://www.sciencedirect.com/science/article/pii/S0166223699014976
    [5] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058197/
    [6] http://www.nature.com/nrn/journal/v2/n6/abs/nrn0601_425a.html
    [7] http://www.sciencedirect.com/science/article/pii/S0166223605000998
    [8] http://www.ncbi.nlm.nih.gov/pubmed/24575048
    [9] http://www.jneurosci.org/content/3/4/773.short
     
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  2. jcsd
  3. Back in the day, roughly around the turn of the 20th century, all communication between neurons was thought to be electro-electrical, or sort of a "continuous" stream through neurons, essentially equivalent to "gap junction-ish" dynamicism. It was largely through the pioneering work of investigators like Ramón y Cajal, Golgi, and Brodmann, who developed microscopic histological techniques and selective neuron staining methods that the chemical synapse was identified.

    Through many more studies over the decades, it was found that the best way to model brain function was as a "contiguous" network of individual neurons communicating through chemical synapses rather than a continuous network communicating through the equivalence of what could be termed gap junction connectivity.

    Referring back to the previous thread you referred to, what is the evidence that brain and behavior is regulated through chemical synapses and not gap junction dynamics? Well, we can start with the entire psychopharmeucetical industry and the literature it embodies. Pharmico-kinetics works primarily through synaptic receptor inhibition, agonism, reuptake inhibition, second messenger system potentiation via neuromodulation, etc. As far as motor expression is concerned, twitch fiber synchronization it is regulated by monoamine dopamine in the frontal cortex and basal ganglia, and by acetylecholine in the motor effectors, each of which work through the chemically modifiable synapse.

    And that is the key, modifiable. From what I know of gap junctions or ephaptic coupling mechanisms in general, there is no mechanism for the generation of a modifiable synapse that could be seen to affect learning or behavior in any sort of significant or salient plastic manner.

    With the 10's of thousands of articles on the subject going back over the decades, of course your going to find a few articles raising a question as to whether other, not so frequently considered, elements of brain function could be making an important contribution. These outlier models crop up in neurobiology just as they do in theoretical physics. And, just as in theoretical physics, they typically stick around for years without shifting the existing zeitgeist, and that's typically because they are just wrong.

    IMHO, this is what we are seeing here in these threads with the gap junction argument, and especially with madness's introduction of the participation of astrocytes, which are glial cells, in the participation of brain dynamics. These ideas, again, typically crop up when progress in a certain field stagnates and researchers look for alternative explanations. The glial cell contribution to brain function has been around for well over a decade now and I'm sure one could pull out a few articles arguing for it. And the thing is, yes, they do participate in brain function because they support the neurons that are actually doing the real work. Do they do real work themselves? Maybe in a sense. But the important point is that that contribution is negligible relative to the massive and significant role in brain dynamics that is accomplished through actual neurons and their electrochemical synapses.

    Again, as I said in the previous thread, the only behaviorally significant effect to brain dynamics that gap junctions seem to confer are a contribution to local synchronization effects in neuronal tissue who's relevance is still controversial.
     
  4. Pythagorean

    Pythagorean 4,576
    Gold Member

    I don't agree with this implied mutual exclusiveness. Certainly, chemical synapses dominate brain dynamics (in adults) but the point here is that gap junctions still play important functional roles and are not as trivial and insignificant as ephaptic coupling. You don't have to convince me of the evidence for chemical synapses playing a role.

    The hemichannels of gap junctions are made of innexins, connexins, and pannexins (depending on species) and the individual hemichannels can be modulated to open, close, or rectify (only allow current through one direction) . Further, individual cells can regulate the amount of gap junctions present to change the coupling strength. [1][2]


    [1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307687/
    [2] http://www.sciencedirect.com/science/article/pii/S0005273612001848

    This approaches the no true scottsman fallacy. You can start dividing functions into "real" and "not real" and then anytime a function is demonstrated, you can just say "but that's not real work". It's not a very productive approach to discussion, imo.
     
  5. Pythagorean

    Pythagorean 4,576
    Gold Member

    As for astrocytes, my understanding is that it's known accepted that they release D-Serine (a necessary co-agonist for activation of NMDA receptors) [1] and can also release the neurotransmitter glutamate at the tripartite synapse [2]. They've also been shown to regulate Fabp7 and PSD through transcription [3].

    [1] http://www.ncbi.nlm.nih.gov/pubmed/23485803
    [2] http://www.ncbi.nlm.nih.gov/pubmed/16221850
    [3] http://www.ncbi.nlm.nih.gov/pubmed/18286188

    But perhaps we should start an astrocyte thread as well :)
     
  6. I didn't say that they don't do any real work. I said maybe they do in some tangential sense. My theme was about "preponderance of the evidence" for what does the "lions" share of real work, of you re-read it.

     
  7. See, this is exactly the point I was trying to make. Now I'm in a position, as in the previous thread, where I'd have to prove a negative to win the argument, which, of course I can't do. That argument being that gap junctions or glial cell activity have never participated significantly in any sort of brain process.

    So, I'll just stick to my above argument, for the record.

    Although, I'd have to say that I didn't know C. Elegans got constipated?! Who would have guessed?

    I'd say that enough of a reason right there to keep your gap junctions running effectively:smile:.
     
  8. Pythagorean

    Pythagorean 4,576
    Gold Member

    I think what is interesting about the contribution of things like astrocytes* and gap junctions is that their contribution to processing (not support roles) is an open question and there's lots of evidence suggesting it's worth investigating. I guess chemical synapses are boring to me. I do find the diversity and classifications of GABAergic interneurons in the cortex very interesting.

    I also think an interesting aspect of biology, in general, is how support roles aren't cleanly separable from processing roles. For example (in addition to electrical synapses and astrocytes), ATP functions both as an energy source (support) and a signaling molecule (processing).

    *astrocytes are the only glial cells I know of that have significant evidence for their contributions to processing.
     
  9. Have you seen this? http://www.pnas.org/content/early/2014/07/23/1410893111.abstract

    Seems like pretty strong evidence for the role of astrocytes in circuit dynamics and cognition.
     
  10. Pythagorean

    Pythagorean 4,576
    Gold Member

    I didn't read the paper, just the abstract. I agree somewhat with Dirac Pool about something like this:

    Now, they may show how the role is a processing role and not a support role, but from just the sentence above, it could very well be a support role, and without the support of the astrocytes, the neuron responsible for the activity can't function.

    The paper that sticks out that I have read on astrocytes modulating glutamate release at the tripartite synapse carefully went through each process in the chain (I believe they found it effected nr2b receptors on the postsynaptic cell, leading to LTP in response to ATP signaling on the astrocytes y2p1 receptors). For each process, they presented their evidence.

    I believe this is the paper, but not on a privileged account currently:
    http://www.nature.com/neuro/journal/v10/n3/abs/nn1849.html
     
  11. Sounds like a false dichotomy to me. Can you provide a suitable definition of support versus processing roles? Couldn't similar arguments be made about interneurons etc.?
     
  12. Pythagorean

    Pythagorean 4,576
    Gold Member

    There's no dichotomy implied. In fact, earlier in the thread:

    The point is not that it's one or the other. The point is that evidence for processing needs to be presented; for example, if you remove all the blood from an organism and present it with a math test (which it then fails, having no blood) then conclude that blood is important to mathematics, you'd be technically correct, but it wouldn't be a very meaningful statement. Blood doesn't participate in the processing itself, it merely makes sure other cells have the resources they need to do the processing.
     
  13. Right, but again you need to provide a definition of support vs processing, otherwise it's not possible to provide evidence.
     
  14. Pythagorean

    Pythagorean 4,576
    Gold Member

    It's actually quite common terminology in the literature. It often boils down to the debate of whether the role is "just supporting" or not. That is the nature of DiracPool's criticism. It's not a new concept.

    Briefly, processing serves to relay information, whereas support is the provision of energy, structural integrity, or components for building proteins. Of course, there is no dichotomy... for instance, actin provides structural support for the cell, but actions on actin (breaking of the structures) can also trigger actin constructing and deconstructing processes (a signaling role).
     
  15. In that case, I'm not sure why you would consider vesicular release of neurotransmitter by astrocytes to be a support rather than processing role.
     
  16. The most straightforward definition of support versus processing is the criterion of "does the cell support an action potential?" If it does, it's typically designated a neuron, if it doesn't it's typically designated neuroglia. Glia, meaning glue, which holds or glues the processing neurons together and supports them through supplying of nutrients, insulating the axons, processing metabolic waste, etc.

    Does that mean that there's never been an instance when an otherwise designated glial cell has participated in some sort of information processing? Probably not.

    http://en.wikipedia.org/wiki/Glial_cell

    However, when conducting perceptual or behavioral trials in test animals, you're going to get a lot more relevant information on network dynamics by recording spike trains and local field potentials from actual neurons rather than targeting the glial cells.
     
  17. Well if you define processing roles to be generating action potentials, then it's trivially true that only neurons do processing. However, glia "support" action potentials in other cells (by vesicular release of neurotransmitter). And, as shown in the recent study I linked to, this process has a marked effect on the gamma frequency LFP and on novel object recognition. I find this to be convincing evidence of a processing role, but clearly it will depend on your definitions.
     
  18. atyy

    atyy 9,759
    Science Advisor

    It shows that astrocytes can be used to control neural activity. But just going by the abstract, doesn't it depend on tetanus neurotoxin being artifically expressed in astrocytes?
     
  19. The tetanus neurotoxin was selectively expressed in order to disrupt vesicular release. The resulting decrease in gamma power and novel object recognition demonstrates that this vesicular release is somehow implicated in those processes. This is similar to lesion studies, where you destroy part of the brain and see what effect it has, but more targeted.
     
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  20. That's a fair point. It also depends on what you're interested in. In college my initial interest in neurobiology was in receptor chemistry. However, after a while it shifted to electophysiology when I realized that the important processing that the brain does is in the mesoscopic dynamic range revealed in LFP and small surface cortical arrays. These recordings average out the participation of anywhere between 10's of thousands to 10's of millions of individual neurons and several orders of magnitude more synapses than that.

    Thus, whether or not gap junctions or glial cells play a role in information processing and what the extent of that is I am not really an expert on and, frankly, am not so concerned about. At the end of the day what is important is the network dynamics. These dynamics are self-organized, and every aspect of the neuropil plays an important role, gap junctions, glia, neurons, blood vessels and the like. They all work together to generate and sustain the important convergent dynamics and oscillations in the cortex.
     
  21. atyy

    atyy 9,759
    Science Advisor

    Thanks! Is the vesicular release continuous?

    Incidentally, that reminds me of another one I saw http://www.ncbi.nlm.nih.gov/pubmed/23012414, because the paper you mentioned uses carbachol, which IIRC affects acetylcholine.
     
    Last edited: Aug 11, 2014
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