The Synapse
How neurons communicate with each other at synapses
Topics:
Chemical vs. electrical synapses, action potential, neurotransmitters, excitatory synapses, inhibitory synapses, spatial summation, temporal summation, depolarization, hyper-polarization, synaptic signaling, axon terminals, ligands ion channels
Introduction
A single neuron, or nerve cell, can do a lot! It can maintain a resting potential—voltage across the membrane.
It can fire nerve impulses, or action potentials. And it can carry out the metabolic processes required to stay alive.
A neuron’s signaling, however, is much more exciting—no pun intended!—when we consider its interactions with other neurons.
Individual neurons make connections to target neurons and stimulate or inhibit their activity, forming circuits that can process incoming information and carry out a response.
How do neurons “talk” to one another?
The action happens at the synapse, the point of communication between two neurons or between a neuron and a target cell, like a muscle or a gland.
At the synapse, the firing of an action potential in one neuron—the presynaptic, or sending, neuron—causes the transmission of a signal to another neuron—the postsynaptic, or receiving, neuron—making the postsynaptic neuron either more or less likely to fire its own action potential.
In this article, we’ll take a closer look at the synapse and the mechanisms neurons use to send signals across it.
To get the most out of this article, you may want to learn about neuron structure and action potentials first.
Electrical or chemical transmission?
At the end of the 19th and beginning of the 20th century, there was a lot of controversy about whether synaptic transmission was electrical or chemical.
• Some people thought that signaling across a synapse involved the flow of ions directly from one neuron into another—electrical transmission.
• Other people thought it depended on the release of a chemical from one neuron, causing a response in the receiving neuron—chemical transmission.
We now know that synaptic transmission can be either electrical or chemical—in some cases, both at the same synapse!
Chemical transmission is more common, and more complicated, than electrical transmission. So, let’s take a look at chemical transmission first.
Overview of transmission at chemical synapses
Chemical transmission involves release of chemical messengers known as neurotransmitters.
Neurotransmitters carry information from the pre-synaptic—sending—neuron to the post-synaptic—receiving—cell.
As you may remember from the article on neuron structure and function, synapses are usually formed between nerve terminals—axon terminals—on the sending neuron and the cell body or dendrites of the receiving neuron.
A single axon can have multiple branches, allowing it to make synapses on various postsynaptic cells.
Similarly, a single neuron can receive thousands of synaptic inputs from many different presynaptic—sending—neurons.
Inside the axon terminal of a sending cell are many synaptic vesicles. These are membrane-bound spheres filled with neurotransmitter molecules.
There is a small gap between the axon terminal of the presynaptic neuron and the membrane of the postsynaptic cell, and this gap is called the synaptic cleft.
When an action potential, or nerve impulse, arrives at the axon terminal, it activates voltage-gated calcium channels in the cell membrane.
CA2+ which is present at a much higher concentration outside the neuron than inside, rushes into the cell.
The CA2+ allows synaptic vesicles to fuse with the axon terminal membrane, releasing neurotransmitter into the synaptic cleft.
The molecules of neurotransmitter diffuse across the synaptic cleft and bind to receptor proteins on the postsynaptic cell.
Activation of postsynaptic receptors leads to the opening or closing of ion channels in the cell membrane.
This may be depolarizing —make the inside of the cell more positive—
or hyperpolarizing —make the inside of the cell more negative— depending on the ions involved.
In some cases, these effects on channel behavior are direct: the receptor is a ligand-gated ion channel, as in the diagram above.
In other cases, the receptor is not an ion channel itself but activates ion channels through a signaling pathway.
See the article on neurotransmitters and receptors for more info.
Excitatory and inhibitory postsynaptic potentials
When a neurotransmitter binds to its receptor on a receiving cell, it causes ion channels to open or close.
This can produce a localized change in the membrane potential—voltage across the membrane—of the receiving cell.
In some cases, the change makes the target cell more likely to fire its own action potential. In this case, the shift in membrane potential is called an excitatory postsynaptic potential, or EPSP. In other cases, the change makes the target cell less likely to fire an action potential and is called an inhibitory postsynaptic potential, or IPSP.
Excitatory Postsynaptic Potential (EPSP)
An EPSP is depolarizing: it makes the inside of the cell more positive, bringing the membrane potential closer to its threshold for firing an action potential.
Sometimes, a single EPSP isn’t large enough to bring the neuron to threshold, but it can sum together with other EPSPs to trigger an action potential.
Inhibitory Postsynaptic Potential (IPSP)
IPSPs have the opposite effect. That is, they tend to keep the membrane potential of the postsynaptic neuron below threshold for firing an action potential. IPSPs are important because they can counteract, or cancel out, the excitatory effect of EPSPs.
Spatial and temporal summation
How do EPSPs and IPSPs interact? Basically, a postsynaptic neuron adds together, or integrates, all of the excitatory and inhibitory inputs it receives and “decides” whether to fire an action potential.
The integration of postsynaptic potentials that occur in different locations
—but at about the same time—is known as spatial summation.
The integration of postsynaptic potentials that occur in the same place
—but at slightly different times—is called temporal summation.
For instance, let’s suppose that excitatory synapses are made on two different dendrites of the same postsynaptic neuron, as shown below.
Neither synapse can produce an EPSP quite large enough to bring the membrane potential to threshold at the axon hillock—the place where the action potential is triggered, boxed below.
If both subthreshold EPSPs occurred at the same time, however, they could sum, or add up, to bring the membrane potential to threshold.
Spatial summation
On the other hand, if an IPSP occurred together with the two EPSPs, it might prevent the membrane potential from reaching threshold and keep the neuron from firing an action potential.
These are examples of spatial summation.
Temporal summation
A key point is that postsynaptic potentials aren’t instantaneous: instead, they last for a little while before they dissipate.
If a presynaptic neuron fires quickly twice in row, causing two EPSPs, the second EPSP may arrive before the first one has dissipated, bumping the membrane potential above threshold.
This is an example of temporal summation.
Signal termination
A synapse can only function effectively if there is some way to “turn off” the signal once it’s been sent.
Termination of the signal lets the postsynaptic cell return to its normal resting potential, ready for new signals to arrive.
For the signal to end, the synaptic cleft must be cleared of neurotransmitter. There are a few different ways to get this done.
The neurotransmitter may be broken down by an enzyme, it may be sucked back up into the presynaptic neuron, or it may simply diffuse away.
In some cases, neurotransmitter can also be “mopped up” by nearby glial cells—not shown in the diagram below.
Anything that interferes with the processes that terminate the synaptic signal can have significant physiological effects.
For instance, some insecticides kill insects by inhibiting an enzyme that breaks down the neurotransmitter acetylcholine.
On a more positive note, drugs that interfere with reuptake of the neurotransmitter serotonin in the human brain are used as antidepressants, for example, Prozac.
What are the benefits of chemical synapses?
Chemical synapses are flexible.
If you’ve learned about action potentials, you may remember that the action potential is an all-or-none response. That is, it either happens at its full strength, or it doesn’t happen at all.
Synaptic Signaling
Synaptic signaling, on the other hand, is much more flexible. For instance, a sending neuron can “dial up” or “dial down” the amount of neurotransmitter it releases in response to the arrival of an action potential.
Similarly, a receiving cell can alter the number of receptors it puts on its membrane and how readily it responds to activation of those receptors. These changes can strengthen or weaken communication at a particular synapse.
Presynaptic and postsynaptic cells can dynamically change their signaling behavior based on their internal state or the cues they receive from other cells.
Synaptic Plasticity
This type of plasticity, or capacity for change, makes the synapse a key site for altering neural circuit strength and plays a role in learning and memory. Synaptic plasticity is also involved in addiction.
In addition, different presynaptic and postsynaptic cells produce different neurotransmitters and neurotransmitter receptors, with different interactions and different effects on the postsynaptic cell.
For more information, take a look at the article on neurotransmitters and receptors.
Electrical synapses
At electrical synapses, unlike chemical synapses, there is a direct physical connection between the presynaptic neuron and the postsynaptic neuron. This connection takes the form of a channel called a gap junction, which allows current—ions—to flow directly from one cell into another.
Electrical synapses transmit signals more rapidly than chemical synapses do. Some synapses are both electrical and chemical. At these synapses, the electrical response occurs earlier than the chemical response.
What are the benefits of electrical synapses?
For one thing, they’re fast—which could be important, say, in a circuit that helps an organism escape from a predator. Also, electrical synapses allow for the synchronized activity of groups of cells. In many cases, they can carry current in both directions so that depolarization of a postsynaptic neuron will lead to depolarization of a presynaptic neuron. This kind of bends the definitions of presynaptic and postsynaptic!
What are the downsides of electrical synapses?
Unlike chemical synapses, electrical synapses cannot turn an excitatory signal in one neuron into an inhibitory signal in another. More broadly, they lack the versatility, flexibility, and capacity for signal modulation that we see in chemical synapses.
Works cited
References
Kandel, E.R., J. H. Schwartz, and T. M. Jessell. “An Introduction to Synaptic Transmission.” In Essentials of Neuroscience and Behavior, 179-195. Norwalk: Appleton & Lange, 1995.
Loewi, Otto. “Nobel Lecture: The Chemical Transmission of Nerve Action.” NobelPrize.org. Accessed March 22, 2016. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1936/loewi-lecture.html.
Nicholls, J.G., A. R. Martin, B. G. Wallace, and P. A. Fuchs. “Principles of Direct Synaptic Transmission.” In From Neuron to Brain, 155-176. 4th ed. Sunderland: Sinauer Associates, 2001.
Openstax College, Biology. “How Neurons Communicate.” OpenStax CNX. Last modified February 29, 2016. http://cnx.org/contents/GFy_h8cu@10.4:cs_Pb-GW@5/How-Neurons-Communicate.
Pereda, Alberto E. “Electrical Synapses and Their Functional Interactions with Chemical Synapses.” Nature Reviews Neuroscience 15 (2014): 250-263. http://dx.doi.org/10.1038/nrn3708.
Purves, D., G. J. Augustine, D. Fitzpatrick, L. C. Katz, A.-S. LaMantia, and J. O. McNamara. “Synaptic Transmission.” In Neuroscience, 85-98. Sunderland: Sinauer Associates, 1997.
Reece, Jane B., Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, and Robert B. Jackson. “Neurons Communicate with Other Cells at Synapses.” In Campbell Biology, 1076. 10th ed. San Francisco: Pearson, 2011.
Sadava, David E., David M. Hillis, H. Craig Heller, and May Berenbaum. “How Do Neurons Communicate with Other Cells?” In Life: The Science of Biology, 956-962. 9th ed. Sunderland: Sinauer Associates, 2009.
Suggestions for further reading
Dale, Henry. “Nobel Lecture: Some Recent Extensions of the Chemical Transmission of the Effects of Nerve Impulses.” NobelPrize.org. Accessed March 22, 2016. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1936/dale-lecture.html.
Loewi, Otto. “Nobel Lecture: The Chemical Transmission of Nerve Action.” NobelPrize.org. Accessed March 22, 2016. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1936/loewi-lecture.html.
Sakmann, Bert. “Sir Bernard Katz. 26 March 1911 – 20 April 2003.” Biogr. Mems Fell. R. Soc. 53 (2007): 185-202. http://dx.doi.org/10.1098/rsbm.2007.0013.
Neurotransmitters and receptors
Different classes of neurotransmitters, and different types of receptors they bind to.
Introduction
Did you know there are billions of neurons—and trillions of synapses—in your amazing brain? (No wonder you can learn anything, including neurobiology!) Most of your synapses are chemical synapses, meaning that information is carried by chemical messengers from one neuron to the next.
In the article on synapses, we discussed how synaptic transmission works. Here, we’ll focus on neurotransmitters, the chemical messengers released from neurons at synapses so that they can “talk” to neighboring cells. We’ll also look at the receptor proteins that let the target cell “hear” the message.
Neurotransmitters: Conventional and unconventional
There are many different kinds of neurotransmitters, and new ones are still being discovered!
Over the years, the very idea of what makes something a neurotransmitter has changed and broadened.
Because the definition has expanded, some recently discovered neurotransmitters may be viewed as “nontraditional” or “unconventional” (relative to older definitions).
We’ll discuss these unconventional neurotransmitters at the end of article. For now, let’s start out by discussing the conventional ones.
Conventional neurotransmitters
The chemical messengers that act as conventional neurotransmitters share certain basic features. They are stored in synaptic vesicles, get released when CA2+ enters the axon terminal in response to an action potential, and act by binding to receptors on the membrane of the postsynaptic cell.
The conventional neurotransmitters can be divided into two main groups: small molecule neurotransmitters and neuropeptides.
Small molecule neurotransmitters
The small molecule neurotransmitters are (not too surprisingly!) various types of small organic molecules.
They include:
The amino acid neurotransmitters glutamate, GABA (γ-aminobutyric acid), and glycine. All of these are amino acids, though GABA is not an amino acid that’s found in proteins.
The biogenic amines dopamine, norepinephrine, epinephrine, serotonin, and histamine, which are made from amino acid precursors. More about the biogenic amines
The purinergic neurotransmitters ATP and adenosine, which are nucleotides and nucleosides. More about purinergic neurotransmitters
Acetylcholine, which does not fit into any of the other structural categories, but is a key neurotransmitter at neuromuscular junctions (where nerves connect to muscles), as well as certain other synapses.
Neuropeptides
The neuropeptides are each made up of three or more amino acids and are larger than the small molecule transmitters. There are a great many different neuropeptides. Some of them include the endorphins and enkephalins, which inhibit pain; Substance P, which carries pain signals; and Neuropeptide Y, which stimulates eating and may act to prevent seizures.
A neurotransmitter’s effects depend on its receptor
Some neurotransmitters are generally viewed as “excitatory,” making a target neuron more likely to fire an action potential. Others are generally seen as “inhibitory,” making a target neuron less likely to fire an action potential.
For instance:
• Glutamate is the main excitatory transmitter in the central nervous system.
• GABA is the main inhibitory neurotransmitter in the adult vertebrate brain.
• Glycine is the main inhibitory neurotransmitter in the spinal cord.
However, “excitatory” and “inhibitory” aren’t really clear-cut bins into which we can sort neurotransmitters.
Instead, a neurotransmitter can sometimes have either an excitatory or an inhibitory effect, depending on the context.
How can that be the case? As it turns out, there isn’t just one type of receptor for each neurotransmitter. Instead, a given neurotransmitter can usually bind to and activate multiple different receptor proteins.
Whether the effect of a certain neurotransmitter is excitatory or inhibitory at a given synapse depends on which of its receptor(s) are present on the postsynaptic (target) cell.
Example: Acetylcholine
Let’s make this more concrete by looking at an example.
The neurotransmitter acetylcholine is excitatory at the neuromuscular junction in skeletal muscle, causing the muscle to contract. In contrast, it is inhibitory in the heart, where it slows heart rate.
These opposite effects are possible because two different types of acetylcholine receptor proteins are found in the two locations.
The acetylcholine receptors in skeletal muscle cells are called nicotinic acetylcholine receptors. They are ion channels that open in response to acetylcholine binding, causing depolarization of the target cell. More info
The acetylcholine receptors in heart muscle cells are called muscarinic acetylcholine receptors. They are not ion channels, but trigger signaling pathways in the target cell that inhibit firing of an action potential.
Types of neurotransmitter receptors
As the example above suggests, we can divide the receptor proteins that are activated by neurotransmitters into two broad classes:
• Ligand-activated ion channels: These receptors are membrane-spanning ion channel proteins that open directly in response to ligand binding.
• Metabotropic receptors: These receptors are not themselves ion channels. Neurotransmitter binding triggers a signaling pathway, which may indirectly open or close channels (or have some other effect entirely).
Ligand-activated ion channels
The first class of neurotransmitter receptors are ligand-activated ion channels, also known as ionotropic receptors. They undergo a change in shape when neurotransmitter binds, causing the channel to open. This may have either an excitatory or an inhibitory effect, depending on the ions that can pass through the channel and their concentrations inside and outside the cell. Ligand-activated ion channels are large protein complexes. They have certain regions that are binding sites for the neurotransmitter, as well as membrane-spanning segments that make up the channel.
Ligand-activated ion channels typically produce very quick physiological responses. Current starts to flow (ions start to cross the membrane) within tens of microseconds of neurotransmitter binding, and the current stops as soon as the neurotransmitter is no longer bound to its receptors. In most cases, the neurotransmitter is removed from the synapse very rapidly, thanks to enzymes that break it down or neighboring cells that take it up.
Metabotropic receptors
Activation of the second class of neurotransmitter receptors only affects ion channel opening and closing indirectly. In this case, the protein to which the neurotransmitter binds—the neurotransmitter receptor—is not an ion channel. Signaling through these metabotropic receptors depends on the activation of several molecules inside the cell and often involves a second messenger pathway. Because it involves more steps, signaling through metabotropic receptors is much slower than signaling through ligand-activated ion channels.
Some metabotropic receptors have excitatory effects when they’re activated (make the cell more likely to fire an action potential), while others have inhibitory effects.
Often, these effects occur because the metabotropic receptor triggers a signaling pathway that opens or closes an ion channel.
Alternatively, a neurotransmitter that binds to a metabotropic receptor may change how the cell responds to a second neurotransmitter that acts through a ligand-activated channel.
Signaling through metabotropic receptors can also have effects on the postsynaptic cell that don’t involve ion channels at all.
Conventional neurotransmitters and their receptor types
Neurotransmitter
Ligand-activated ion channel receptor(s)?
Metabotropic receptor(s)?
Amino acids
GABA
Yes (inhibitory)
Yes
Glutamate
Yes (excitatory)
Yes
Glycine
Yes (inhibitory)
Biogenic amines
Dopamine
Yes
Norepinephrine
Yes
Epinephrine
Yes
Serotonin
Yes (excitatory)
Yes
Histamine
Yes
Purinergic
Adenosine
Yes
ATP
Yes (excitatory)
Yes
Acetylcholine
Yes (excitatory )
Yes
Neuropeptides (many)
Yes
This table isn’t a comprehensive listing, but it does cover some of the most well-known conventional neurotransmitters.
Unconventional neurotransmitters
All of the neurotransmitters we have discussed so far can be considered “conventional” neurotransmitters. More recently, several classes of neurotransmitters have been identified that don’t follow all of the usual rules. These are considered “unconventional” or “nontraditional” neurotransmitters.
Two classes of unconventional transmitters are the endocannabinoids and the gasotransmitters (soluble gases such as nitric oxide, Nitric Oxide [NO) and Carbon Monoxide [CO].
These molecules are unconventional in that they are not stored in synaptic vesicles and may carry messages from the postsynaptic neuron to the presynaptic neuron.
Also, rather than interacting with receptors on the plasma membrane of their target cells, the gasotransmitters can cross the cell membrane and act directly on molecules inside the cell.
Other unconventional messengers will probably be discovered as we learn more and more about how neurons work. As these new chemical messengers are discovered, we may have to further change our idea of what it means to be a neurotransmitter.
Works cited:
Additional references:
Acetylcholine. (2016, April 5). Retrieved April 27, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Acetylcholine.
Acetylcholine receptors. (n.d.) in InterPro. Retrieved April 27, 2016 from https://www.ebi.ac.uk/interpro/potm/2005_11/Page2.htm.
Blaustein, M.P., Kao, J.P.Y., and Matteson, D.R. (2012). Unconventional neurotransmitters modulate many complex physiological responses. In Cellular physiology and neurophysiology (2nd ed., pp 202-203). Philadelphia, PA: Mosby, Inc.
Deutch, A.Y. (2013). Neurotransmitters. In Squire, L.R., Berg, D., Bloom, F.E., du Lac, S., Ghosh, A., and Spitzer N.C. (Eds.), Fundamental neuroscience (4th ed., pp. 117-138). Waltham, MA: Academic Press.
Kandel, E.R., Schwartz, J.H., and Jessell, T.M. (1995). Neurotransmitters. In Essentials of neuroscience and behavior (pp. 31-35). Norwalk, CT: Appleton & Lange.
Muscarinic acetylcholine receptor. (2016, February 12). Retrieved April 27, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor.
Nicholls, J.G., Martin, A.R., Wallace, B.G., and Fuchs, P.A. (2001). Cellular and molecular biochemistry of synaptic transmission: Neurotransmitters. In From neuron to brain (4th ed., pp. 244-247). Sunderland, MA: Sinauer Associates.
Nicotinic acetylcholine receptor. (2016, March 21). Retrieved April 27, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor.
Openstax College, Biology. (2016, February 29). How neurons communicate. In OpenStax CNX. Retrieved from http://cnx.org/contents/GFy_h8cu@10.4:cs_Pb-GW@5/How-Neurons-Communicate.
Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.-S., and McNamara, J.O. (1997). Neurotransmitters. In Neuroscience (pp. 99-119). Sunderland, MA: Sinauer Associates.
Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.-S., and McNamara, J.O. (1997). Neurotransmitter receptors and their effects. In Neuroscience (pp. 121-144). Sunderland, MA: Sinauer Associates.
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Neurons communicate with other cells at synapses. In Campbell biology (10th ed., p. 1076). San Francisco, CA: Pearson.
Sadava, D. E., Hillis, D.M., Heller, H.C., and Berenbaum, M.R. (2009). How do neurons generate and transmit electrical signals? In Life: The science of biology (9th ed., pp. 948-956). Sunderland, MA: Sinauer Associates.
Waxham, M.N. (n.d). Neuropeptides and nitric oxide. In Neuroscience online. Retrieved March 22, 2016 from http://neuroscience.uth.tmc.edu/s1/chapter14.html.
Waxham, M.N. (2013). Neurotransmitter receptors. In Squire, L.R., Berg, D., Bloom,
F.E., du Lac, S., Ghosh, A., and Spitzer N.C. (Eds.), Fundamental neuroscience (4th ed., pp. 163-187). Waltham, MA: Academic Press.
Suggestions for further reading:
Snyder, S.H. (2009). Neurotransmitters, receptors, and second messengers galore in 40 years. In The Journal of Neuroscience, 29, 12717-12721. http://dx.doi.org/10.1523/JNEUROSCI.3670-09.2009.
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