Three’s Company: The tripartite synapse

We tend to think of scientific discoveries as discrete events or moments in time. Newton’s falling apple was the birth of gravity, while Archimede’s bath time revelation and subsequent cries of “Eureka!” in the streets gave us a new way to determine the density of irregular objects. In truth, scientific discoveries are rarely easy to pin down; scientific research is a long, slow process, and each small discovery is like a single piece in a vast puzzle of knowledge. Sometimes it takes years of work and research to develop an understanding of a phenomenon, as in the case of the tripartite synapse.

In 1999, four scientists got together to write what’s known as a review article. In a review, scientists don’t do experiments themselves, but instead read a lot of scientific papers and pull all of that information into a summary of current research, highlighting important conclusions and considerations. The review in question, called “Tripartite synapses: glia, the unacknowledged partner” (1), established the concept of the tripartite synapse.

Your millions of neurons communicate with one another by sending signals across the gaps between cells, called synapses. The electrical signal from within the cell is translated into a chemical signal using tiny molecules called neurotransmitters. The pre-synaptic neuron spits these transmitters into the synapse, where they float across and bind to receptors on the post-synaptic neuron. The binding of transmitter provides the post-synaptic cell with some information about how it should respond to the signal, and it reacts accordingly. In traditional illustrations of the neuronal synapse, you generally only see two pieces: the pre-synapse from the neuron sending the signal, and the post-synapse of the neuron receiving it, as in this image:

Figure 1: A traditional illustration of a synapse. Source: Wikimedia Commons

Unfortunately, diagrams like this leave out a very important third component of most synapses: the astrocyte.

Figure 2: The tripartite synapse. Source: Allen & Barres, Nature, 2009.

Astrocytes were so named because of their “starry” appearance. These cells have many fine, delicate tips that tile across your brain; your astrocytes don’t overlap (check out Figure 3!), so each astrocyte is responsible for controlling its own domain. Many (or possibly even most) of the synapses in your brain are wrapped up in an astrocytic process, with each astrocyte wrapping up many synapses.

Figure 3: Genetically engineered to show up in bright colors, these “brainbow” astrocytes are tiled across the brain. The dark, round holes are the neurons! Source: Scientific American

In 1999, we were still learning about the roles of astrocytes in the brain. Just two years earlier, Pfrieger and Barres had published their influential paper about how astrocytes affect the formation of synapses in the brain. During this time, many scientists were asking questions about the relationships between astrocytes and the neurons they so closely entwined. Alfonso Araque and his colleagues looked at dozens of studies about the relationship between astrocytes and synapses to get a better idea of how they affect one another. In their review, these scientists discussed several key findings:

  1. Astrocytes can release neurotransmittersGlutamate is probably the most important transmitter your brain uses; it’s found at pretty much every excitatory synapse in your brain. The pre-synaptic neuron releases glutamate, which binds to receptors on the post-synaptic neuron, signalling the post-synaptic neuron to fire. But it turns out, astrocytes can release glutamate too, triggered by rising calcium levels within the cell. On top of that, astrocytes can release ATP, the molecule your cells use as fuel, which here acts as a signal between neighboring astrocytes.
  2. Astrocytes can use glutamate to signal to neurons, affecting their calcium levels. As mentioned above, rising calcium levels in astrocytes can trigger glutamate release. This glutamate release is associated with a corresponding increase in calcium levels in the adjacent neurons. Modulating calcium levels can influence the neuron’s signaling pattern.
  3. Astrocytes can affect synaptic transmission. Because astrocytes wrap around synapses, they seem perfectly placed to play an active role in influencing the communication between neurons. Neuronal activity can directly affect calcium levels in neighboring astrocytes, which can then cycle into the astrocytes signaling back to the neurons through glutamate release. This released glutamate binds to receptors on the pre-synaptic neuron and inhibit the release of more transmitter. So not only do astrocytes respond to neuronal activity, but they can directly influence it.

With all of this evidence for astrocytes having so much direct and influential cross-talk with the pre- and post-synaptic neurons, the authors concluded that a more accurate picture of the synapse included all three elements, setting the stage for the tripartite synapse. Since 1999, we’ve learned a lot more about how neurons talk to astrocytes, and how those astrocytes talk back. I’ll be talking about some of those studies in later blog posts! In the mean time, this review is still helping to shape the way scientists think about the synapse. We now know that the synapse is more complex than we imagined, and that many different elements come together to shape signaling at the synapse. This complexity makes studying the synapse harder – but I think it makes things more exciting, too. Don’t you?

1) Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999 May;22(5):208-15. doi:10.1016/S0166-2236(98)01349-6


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