Why are synapses that are connected to co-transmitting presynaptic vesicles uniformly distributed on the postsynaptic neuron?

Question

This paper on functional implications of co-release and co-transmission says that "Consistent with a co-transmission phenotype, cholinergic synapses are uniformly distributed on the postsynaptic neuron, whereas GABAergic synapses are non-uniformly distributed."

Why is it the case that synapses across which neurotransmitters/modulators are co-transmitted are uniformly distributed? Also, what is the typical morphology of synapses that are co-released?

Answer 1

The paper that you link to cites as reference 32 this paper for the relevant section you quote:

Lee, S., Kim, K., & Zhou, Z. J. (2010). Role of ACh-GABA cotransmission in detecting image motion and motion direction. Neuron, 68(6), 1159-1172.

Importantly, they are contrasting between "co-release", where two different neurotransmitters are released by the same cell by packaging together in the same vesicles, and "co-transmission", where two different neurotransmitters are released by the same cell by packaging them into separate vesicles.

I do not believe or understand the authors to express any substantial importance to the uniform distribution of one of the post-synaptic receptors as evidence for co-transmission over co-release; rather, it is that the distribution of post-synaptic receptors is different for the different neurotransmitters released, which is evidence that they are not released in the same places which means they must be in different vesicles.

It so happens that what makes it most clear that the distribution is different is that receptors for one transmitter are found all over ("uniform") and for the other they are found only in particular locations ("non-uniform"). Other types of difference in distribution would also be evidence for co-transmission.

For this particular pre/post-synaptic pairing, the significance of this arrangement is that it functionally creates a direction selectivity, where a stimulus appearing from one direction triggers inhibition ahead of excitation, such that the cell does not fire, whereas a stimulus from the other direction triggers excitation first so the cell can be driven to fire before inhibition occurs:

Figure 7 from Lee et al 2010

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I highly recommend reading the whole Lee et al paper, as well as these by Fried et al:

Fried, S. I., Münch, T. A., & Werblin, F. S. (2002). Mechanisms and circuitry underlying directional selectivity in the retina. Nature, 420(6914), 411-414.

Fried, S. I., Munch, T. A., & Werblin, F. S. (2005). Directional selectivity is formed at multiple levels by laterally offset inhibition in the rabbit retina. Neuron, 46(1), 117-127.

Lee, S., Kim, K., & Zhou, Z. J. (2010). Role of ACh-GABA cotransmission in detecting image motion and motion direction. Neuron, 68(6), 1159-1172.