Can a neuron be both excitatory and inhibitory?

Hey. I am completely new to neuroscience. While going through W1D1 T2 Bonus section, I had a doubt: can a neuron behave as an excitatory neuron at one point of time and as an inhibitory neuron at another point?

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For the most part - no. We refer to this as Dale’s Law, the consequences being that a neuron will only be excitatory or inhibitory across both time and “receiver” postsynaptic neurons, but sometimes in simplified models we ignore it.

(feel free to ignore the below if it’s unintelligible)

On a technical point the resting voltage will generally determine whether a neurotransmitter will be excitatory or inhibitory. So, GABA during early development might be excitatory but inhibitory later on (iirc, i remember reading this in kandel or somewhere a while back…).

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NO, a neuron type is defined by the transmitter that is released. Excitatory neurons are glutamatergic because they release glutamate and they depolarise the postsynaptic neuron. Inhibitory neurons are GABAergic because they release gamma-amino-butyric acid (GABA). GABA can act as excitatory or inhibitory depending on the postsynaptic cell, and the confusion arive because GABAergic neurons can be excitatory or inhibitory.

In addition, neurons can release more than one neurotransmitter (e.g., glutamate and ATP, glutamate and noradrenaline, GABA and glycine, etc). The actions on the postsynaptic cell are complex, but I am not aware of an excitatory+inhibitory transmitter form the same neuron.

Hope it helps!

Jose

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It seems to be very rare for now but this paper shows pretty convincingly that CCK+/VGlut3+ interneurons in the mouse hippocampus release both GABA & Glutamate with both excitatory and inhibitory effects onto pyramidal cells.

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Mammalian neurons can’t be both excitatory and inhibitory, but neurons of the C. elegans nematode can, and some are!

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I was almost sure that in invertebrates the rule could be different, but that CCK interneurons release both transmitters is incredible! The CA2 hippocampal area is really something very new!

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Actually the paired recordings from the Pelkey et al. paper I referenced are from CA1! It’s fascinating.

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Nothing beats paired-recordings!!

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To reiterate on what @rotem.ruach said, C. elegans do utilize neurons in a much more compact way so they have excitatory GABA receptors (GABA is traditionally an inhibitory transmitter) as referenced here.

It can happen! There are neurons in the ventral tegmental area that co-transmit glutamate and GABA: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843828/

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To add to the points before, not surprisingly the answer seem to be more complicated than yes or no (as is usually the case in bio). Here is a recent article about NT switching with exercise.
Li, H., Spitzer, N.C. Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain. Nat Commun 11, 2195 (2020). https://doi.org/10.1038/s41467-020-16053-7

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I think it might be more precise to say if a neuron provides excitatory vs inhibitory input to another neuron. It will depend on things like the type of receptors the second neuron has, the extracellular solution at the synapse, etc. For example, in developing brain, GABA input can be excitatory as chloride is higher inside; and different types of glutamate receptors can either be excitatory or inhibitory.

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Thanks a ton for the explanation(s) guys. I guess the answer is a NO in case of mammals and YES in some scenarios in case of invertebrates.

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Hi! Maybe I’m wrong, but in the moodel in was about receiving different inputs (not sending!). And neuron can receive both excitatory and inhibitory inputs. And another point I want to mention: we all know that there is a Dale’s rule that one neuron can secrete only one neuromediator (which is generally can be false, but in most cases we can apply it), but the properties of input are determined by particular type of receptors on the receiving neuron. Beautiful example is acetylcholine in PNS: it can both promote skeletal muscle constraction through nAch-cholinoreceptors and have an opposite effect on heart muscle through mAch-receptors. So I can imagine the model with one cholinergic neuron which is both excitatory and inhibitory for different receiving neurons. Correct me if I’m wrong

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There are also serotonergic neurons that can be excitatory and inhibitory. It all also depends on the receptor that the receiving neuron expresses. In flies there are 2 inhibitory serotonin receptors and 3 excitatory serotonin receptors, I think in mammals it is even 14 different receptors. And also some neurons might express several of these receptors…so it might get complicated. Also for Glutamate, there are different receptors in the fly, and excitatory metabotropic receptor and an inhibitory channel.

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And it is more complex that the neurotransmitter that it is being released, but how that neuron interacts with other neurons in its network.

As an example, hilar mossy cells in the hippocampus, excite both basket cells (interneurons) and granule cells (glutamate cells).

So under certain conditions, that neuron can be driving inhibition or excitation.

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Why is it important if it does it?

Unfortunately the answers above are too categorical which is a slippery slope in computational neuroscience! :warning:

  1. When talking about the Glutamatergic and GABAergic neurons, the answer tends to be “no they can’t do both”.
    But the reason we have that is not the presynaptic neuron but rather the post-synaptic neuron.

  2. When talking about other neurotransmitters such as Dopamine and Acetylcholine, the answer is immensely different. In those cases the attention should be shifted to the receptors on the post-synaptic cell.

One of the most important cases where you have the same input but different populations receive it differently is the nigrostriatal pathway in basal ganglia of the brain (basically where movement is regulated). The substantia nigra pars compacta (SNc) gives Dopaminergic connections to the corpus striatum. The striatal Medium Spiny Neurons (MSNs) that have the Dopamine-1-Receptors (D1R) are excited by it (getting EPSP) and the cells with Dopamine-2-Receptors (D2R) are inhibited.
This separation gives rise to the direct and indirect pathways respectively.

For a intro level review of the system you can see this tutorial from KenHub:

And for an example of this key separation of effects in research you can see this paper:
http://dx.doi.org/10.1016/j.neuron.2016.06.010

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Grrreattt discussion guys! Thanks you for your responses. It’d be really helpful if you can help on this thread as well. Project - HCP data - Possible analysis for finding correlation between brain regions. Looking forward to some really interesting responses from you all!!

Just when you thought that this was clear this study shows neutrons that are both excitatory and inhibitory
https://www.nature.com/articles/nn.3840

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