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The textbook examples for an excitatory neurotransmitter is Glutamate, and for an inhibitory neurotransmitter it is GABA.

In my naive understanding, a neuron was inhibitory or excitatory depending on the neurotransmitter it releases onto its postsynaptic partners.

According to this thread, however, a neurotransmitter is not per se excitatory or inhibitory, but this property depends on the postsynaptic receptor it is acting on.

Now this property seems independent of the presynaptic cell - hence, how can we classify the presynaptic cell of being either inhibitory or excitatory (when that is a property of the postsynaptic receptors, which can be either)?

Besides, given that we a huge number of neurons and their connections in each $mm^3$, how can we be sure that the presynaptic's cells action are not mediated by other cells, and the observed inhibition/excitation is not rather a network effect?

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In my naive understanding, a neuron was inhibitory or excitatory depending on the neurotransmitter it releases onto its postsynaptic partners.

This is mostly correct. What remains a question is what makes a given neurotransmitter inhibitory or excitatory. To some extent, that depends on the post-synaptic receptors, but also depends on other conditions: one case mentioned in the linked Q&A that I'll repeat is that GABA is actually excitatory at some times, including during development (and the same thing can happen in certain causes of epilepsy). In that case, the reason is because GABA-A receptors are chloride channels, so the reversal potential for chloride is what matters. If the reversal potential for chloride is more hyperpolarized than threshold, GABA-A is an inhibitory receptor; if the reversal potential for chloride is more depolarized than threshold, GABA-A is an excitatory receptor. Chloride ion concentrations are different during certain stages of development so the role of GABA changes (in development it seems like it is important for development of eventually inhibitory circuitry).

I digress a bit, but I think you've really already encountered all you need to know: labels like "excitatory" and "inhibitory" for a neurotransmitter itself are generalizations that satisfy human preferences for heuristics. It's convenient to talk about GABA as an inhibitory neurotransmitter, because in most cases the major systemic effect of GABA is inhibition. Same with glutamate in the direction of excitation.

Most of the inhibition caused by glutamate is the presynaptic inhibition type discussed in a previous Q&A; that is, it is suppressing the release of glutamate itself. In that sense, glutamatergic inhibition is only as effective as glutamatergic excitation is: the net effect of glutamate will always be excitatory in that system.

Therefore, it is straightforward to consider GABAergic and glutamatergic cells inhibitory and excitatory, respectively.

how can we be sure that the presynaptic's cells action are not mediated by other cells, and the observed inhibition/excitation is not rather a network effect?

The principle way is by pairwise recordings: you record from the presynaptic and postsynaptic cell at the same time, activate the presynaptic cell, and measure the voltage in the postsynaptic cell. These sorts of pairwise recordings are a common tool in neuroscience.

Cancedda, L., Fiumelli, H., Chen, K., & Poo, M. M. (2007). Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. Journal of Neuroscience, 27(19), 5224-5235.

Owens, D. F., Boyce, L. H., Davis, M. B., & Kriegstein, A. R. (1996). Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. Journal of Neuroscience, 16(20), 6414-6423.

Thomson, A. M., & Deuchars, J. (1997). Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro. Cerebral cortex (New York, NY: 1991), 7(6), 510-522.

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  • $\begingroup$ "The principle way is by pairwise recordings: you record from the presynaptic and postsynaptic cell at the same time, activate the presynaptic cell, and measure the voltage in the postsynaptic cell." --> But this is still a correlation analysis. Say you activate cell A and record A and B, how can you exclude A acting on C,D,E...with all kinds of non-trivial interactions then leading to changes in B? Then while A would still be relevant for B, the excitation/inhibition might arise from more complex mechanisms. $\endgroup$
    – Pugl
    Commented Sep 5, 2019 at 22:19
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    $\begingroup$ @Pugl No, it's not a correlation analysis: you stimulate and measure the response. A correlation analysis would just measure activity in both and relate the (spontaneous) spiking times to the voltage. You can base conclusions on latency, use brain slice recordings where spontaneous activity is very low (such that only the cell you are activating is likely to be firing, and especially only that cell is firing time locked to every stimulation trial), in some cases record directly from dendrites and even axons in special synapses. $\endgroup$
    – Bryan Krause ♦
    Commented Sep 5, 2019 at 22:22
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    $\begingroup$ You can use pharmacology to test which transmitters and receptors are involved, directly puff neurotransmitters onto the post synaptic cell and see the same results, you can use imaging to monitor voltage or calcium in real time, you can activate presynaptic terminals with calcium uncaging. Basically decades and decades of neuroscience research. $\endgroup$
    – Bryan Krause ♦
    Commented Sep 5, 2019 at 22:24

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