Introduction

Neurons communicate with other neurons electrochemically.

In my post, How Do Neurons Communicate? Action Potentials (Part 1), I explained the first part of how neurons communicate. If you have not read that post, I recommend reading it to get a better understanding of action potential and how neurons move information along their axon.

In this post, I will cover the second part of how neurons communicate (-chemically). Because neuronal communication has 2 steps involved, I have decided to split each step into 2 different posts so as not to miss important information to provide a deeper understanding of each topic.

After an action potential reaches the axon terminals, a chain of events takes place, causing the release of neurotransmitters that serve as the communication molecules between neurons. These substances create local potentials existing in the postsynaptic neuron after presynaptic transmitters bind to the postsynaptic receptors.

While synaptic transmission (communication via synapse) can be electrical and chemical, I will only explain the chemical process of neurotransmission (Khan Academy, 2018). I will cover the differences between the two types in a separate post.

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What is Synaptic Transmission?

Synaptic transmission is the communication or transfer of information between 2 neurons across the synaptic cleft (gap between neurons where synapse takes place). I like to think of synapses as conversations between 2 neurons.

One point to understand is that chemical synapses do not involve physical contact between neurons.

If you think about a conversation between people, words are transmitted across space where they are received by the ear of the other party involved.

Regarding neurotransmission, the substance that serves as the information molecule is known as a neurotransmitter.

This molecule is released from the presynaptic axon terminals, across the synaptic cleft, and binds to a postsynaptic receptor located on a dendrite where it exerts its effects.

In addition, synaptic transmission doesn’t always occur between the presynaptic neuron’s terminals and the postsynaptic neuron’s dendrites (Watson & Breedlove, 2021). Synapses or connections between two neurons can occur in about 4 different ways. The 4 main ways synapses occur are listed below:

1. Axo-dendritic- synapse between presynaptic axon (terminal) and postsynaptic dendrite (most common).
2. Axo-somatic- synapse between presynaptic axon (terminal) and postsynaptic soma (cell body).
3. Axo-axonic- synapse between presynaptic axon (terminal) and postsynaptic axon (terminal).
4. Dendro-dendritic- synapse between presynaptic dendrite and postsynaptic dendrite (least common).

Now that we have a general idea of how synaptic transmission works, let’s get down to the specific details of how chemical synaptic transmission operates.

How Does Chemical Synaptic Transmission Work?

Phase 1: Trigger

Chemical synaptic transmission can be broken down into 3 separate phases. The first is what I like to call the trigger phase.

As stated in How Do Neurons Communicate? Action Potentials (Part 1), the action potential, which is a rapid reversal of the neuron’s membrane potential, is actively propagated down the axon. This rapid reversal is made possible when a stimulus elicits sodium voltage-gated ion channels (VGICs) to open, causing an influx of sodium, changing the membrane potential (Hedges, 2022).

Once the action potential reaches the axon collaterals and terminals, sodium VGICs are no longer required to carry the information. Instead, a new type of VGIC is initiated and opened.

The change in membrane potential in the axon collateral and terminals triggers VGICs to open and allow an influx of calcium (Ca2+) ions. The calcium ions trigger a sequence of events that eventually lead to the release of the chemical neurotransmitter. According to Holz & Fisher (1999), chemical transmission will not occur unless there is a sufficient supply of Ca2+ ions in the extracellular fluid.

The influx of Ca2+ triggers synaptic vesicles, a lipid membrane sac containing the neurotransmitter, to travel down the axon originating from the neuronal cell body, aka the soma.

Interestingly, the interaction between calcium ions and the vesicles is complex (Hedges, 2022). Calcium VGICs are concentrated near active zones, and once these channels are triggered and calcium is allowed to flow inside the neuron, they interact and bind with an embedded protein(s) on the vesicle.

This bounded protein, synaptogamin, detects calcium levels and changes in shape once calcium binds. The conformational change results in the recruitment of new protein, forming a complex that helps dock vesicles at the active zones.

Phase 2: Release

This is where we begin phase 2, or the release phase.

These vesicles carry the transmitters down the axon to the terminals, where they are released into the synaptic cleft via exocytosis (Holz & Fisher, 1999).

If we break down the word exocytosis in its components, we see Exo- meaning out of, cyt- meaning cell, and -osis meaning the process of. So, if we were to combine these meanings to form one coherent definition, exocytosis is the process of transporting materials out of the cell. In this case, the material we are exporting is neurotransmitters.

The general process of exocytosis is simple.

The synaptic vesicle is a sac made of lipids similar to the neuron’s cell membrane. It approaches the cell membrane at a location known as an active zone. It then fuses with the membrane and releases the stored neurotransmitters into the synaptic cleft.

Once released, neurotransmitters diffuse across the cleft randomly and bind to their matching postsynaptic receptors. They form a Receptor-Ligand Complex (RLC) for a short period of time.

Also, the relationship between specific neurotransmitters and their respective receptors has been likened to that of a key and lock (Watson & Breedlove, 2021). The neurotransmitter, with its specific configuration, acts as the key and can only bind to the appropriate receptor (lock) in order to initiate changes in the postsynaptic neuron.

But, before I discuss postsynaptic effects, it’s important to understand two mechanisms. The first involves the outcome of neurotransmitters after they form the RLC. The second involves the regulation of neurotransmitter release.

First, neurotransmitters do not stay bound continuously (Speller, 2018). They bind, initiate postsynaptic effects, and detach, floating back into the abyss we know as the synaptic cleft. It is in this random drift that a neurotransmitter meets one of three fates:

1. Reuptake- The neurotransmitter(s) can be recycled and reused through the process of reuptake, where transporter proteins help move the neurotransmitter back into the presynaptic neuron.
2. Enzymatic Degradation- It can be broken down by enzymes, leading to inactivation.
3. Diffusion- It can drift off and diffuse into the surrounding areas of extracellular fluid.

In addition, presynaptic neurons have special receptor proteins called autoreceptors. These receptors detect how much neurotransmitter has been released into the synaptic cleft and serve as a feedback system for the neuron itself (Ford, 2014). They regulate the release of neurotransmitters via the modulation of exocytosis.

1. Inhibition – When neurotransmitter levels in the synapse are high, autoreceptors are activated, signalling the neuron to slow down or stop neurotransmitter release. This prevents overstimulation and helps maintain balance.
2. Modulation – When neurotransmitter levels are low or within normal range, autoreceptors are less active or inactive, allowing the neuron to continue releasing neurotransmitters as needed. However, they don’t actively stimulate more release—they simply reduce inhibition.

Phase 3: Effect

Now that the neurotransmitters have crossed the synaptic cleft and bound to their matching receptors, we arrive at the final stage of chemical synaptic transmission: the postsynaptic effect.

Neurotransmitters bind to postsynaptic receptors, forming the RLC. These postsynaptic receptors are also called ligand-gated receptors, as once a ligand binds (i.e. a neurotransmitter) to it, it can have one of two primary effects (Watson & Breedlove, 2021).

If a neurotransmitter binds an ionotropic receptor, it opens an ion channel, causing the neuron to depolarise (raising the membrane potential closer to zero) or hyperpolarise (lowering the membrane potential past rest).

However, if a neurotransmitter binds to a metabotropic receptor, it can indirectly affect the membrane potential through the release of secondary messenger molecules inside the neuron.

Direct or indirect changes in postsynaptic membrane potentials are influenced by multiple factors. The first is the type of local potential that occurs. Postsynaptic potentials (PSPs) are local potentials that are excitatory or inhibitory in their effect. To learn a bit more about local PSPs, read this post: How Do Neurons Communicate? Action Potentials (Part 1).

For example, if a presynaptic neuron is inhibitory, it may stimulate (ionotropic or metabotropic) chloride ion channels in the postsynaptic neuron, causing hyperpolarisation (because chloride has a minus 1 charge).

When the presynaptic neuron is excitatory, it stimulates sodium ion channels in the postsynaptic neuron, causing depolarisation (because sodium has a plus 1 charge).

The second, simply put, is the type of neurotransmitter and receptor, because different kinds of each can influence the response of the postsynaptic neuron.

Inhibitory neurons have the goal of inhibiting the subsequent neuron from initiating an action potential, ultimately stopping that neuron from firing and communicating with other neurons. On the other hand, excitatory neurons increase the chances that subsequent neurons will fire, making sure information is passed on to other neurons.

Furthermore, the effect of a single inhibitory or excitatory input by a presynaptic neuron is usually not enough to initiate or inhibit the postsynaptic neuron from firing. This is because a single neuron receives input from thousands of other neurons in the brain, each with their own inhibitory or excitatory effects (CRAZY!!).

The postsynaptic neuron is engaged in a process called summation, which determines if the axon hillock will initiate an action potential.

Summation is the process of adding together the PSPs that occur across space and time. So, spatial summation is the integrative process where multiple inputs occur at one or close to one time on different locations of the neuron (at different synapses). In other words, it is the addition of PSPs that originate from different locations.

Also, temporal summation is the integrative process where multiple inputs occur in rapid succession or one after the other, but only at one synapse (from the same neuron). In other words, it is the addition of PSPs in one location across time involving only one neuron.

See Table 1 for more information and clarity about the differences between temporal and spatial summation.

Table 1: Features of Temporal & Spatial Summation

Feature	Temporal Summation	Spatial Summation
Definition	Addition of multiple inputs over time at one location or synapse.	Addition of multiple inputs from multiple synapses at the same time.
Input Source	Involves only 1 presynaptic neuron.	Involves multiple presynaptic neurons.
Timing	Inputs arrive in rapid succession (across time– milliseconds).	Inputs arrive at the same point in time.
Effectiveness	More effective if inputs occur close together (in time).	More effective if multiple presynaptic neurons synapse at the same time.
Result	Can initiate an action potential once the threshold is reached.	Can also initiate an action potential if the combined input is strong enough.

If this still seems a little confusing, I want to use an analogy. Think of yourself in a house (preferably your own home, but I don’t judge). Now, your house signifies a neuronal cell body, and the door represents the location of a synapse or where synaptic transmission takes place.

To explain spatial summation, imagine multiple people (acting as a neurotransmitter) knocking on your front, your back, and your side doors at the same time (maybe trying to sell you some girl scout cookies or break into your house). If enough people are swarming your house and knocking on the doors, you might feel excited (not in a good way), which may make you fire a warning shot (an action potential) to scare them away.

To explain temporal summation, imagine it’s only one person knocking on one of your doors, but it’s not just one knock. Instead, it’s multiple fast loud knocks (they really want to sell you some girl scout cookies). Again, this might excite you enough to pull the trigger.

Once enough excitatory inputs accumulate (whether through space, time, or both) and depolarise the neuron to threshold, only then will the neuron’s axon hillock decide to fire an action potential, restarting the process of neuronal communication.

Conclusion

To sum it all up, neurons communicate with each other by firing electrical signals, releasing chemical messengers, and processing synaptic input through summation. It starts with an action potential (an electrical process) that travels down the axon to the terminals. This signal leads to the release of neurotransmitters (chemical messengers) that travel across the synaptic cleft.

These messengers bind to receptors on the postsynaptic neuron and create localised changes in membrane potential. These alterations in membrane potential are then added together across time and space. When the combined input is great enough to reach the neuron’s threshold, a new action potential is initiated and the cycle of communication continues. While complex, this beautiful process underlies everything involving the brain, from thoughts to memory to disorders and behaviour.

References

Ford C. P. (2014). The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience, 282, 13–22. https://doi.org/10.1016/j.neuroscience.2014.01.025

Hedges, V. (2022). Steps in Synaptic Signaling. Openbooks.lib.msu.edu. https://openbooks.lib.msu.edu/introneuroscience1/chapter/neurotransmitter-release/

Holz, R. W., & Fisher, S. K. (1999). Synaptic transmission. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th Edition, 6(6). https://www.ncbi.nlm.nih.gov/books/NBK27911/

Khan Academy. (2018). The synapse. Khan Academy. https://www.khanacademy.org/science/biology/human-biology/neuron-nervous-system/a/the-synapse

Speller, J. (2018). Synaptic Transmission – Clinical Relevance – TeachMePhysiology. TeachMePhysiology. https://teachmephysiology.com/nervous-system/synapses/synaptic-transmission/

Watson, N. V., & S Marc Breedlove. (2021). The mind’s machine: foundations of brain and behavior. Sinauer Associates/Oxford University Press.

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