Astrocytes, the Underrated Stars

[En español]

You usually hear the term “brain cell” referring to neurons, like they’re the only cell type present in the brain. But that’s far from the case. Neurons can be considered the main cellular unit in our nervous system, as they are the cells that transfer the information by means of electrical and chemical signals. I won’t argue the fact that neurons are tremendously important, but I will fight you for neglecting the other “brain cells” that make up our brain.

In fact, half of our brain cell content is actually “glia”. This term includes oligodendrocytes, microglia, and astrocytes, which are three different non-neuronal cell types found in the brain as well as the other cells that make up the blood vessels that run through the brain. “Glia” is a word derived from Greek that means “glue”, as the assumption was that this mass of non-neuronal cells were in the brain with the sole function of keeping everything together, everything “glued”.

However, glial cells are quite diverse, and they have more than structural “gluing” and supportive functions.

Astrocytes are the most abundant glial cell type. Their name, also from Greek, means “star cell”. Among their various functions they provide nutrients and physical support to neurons, and are also in charge of maintaining the delicate chemical balance in the brain. Astrocytes have received much attention as they make up the so-called glial scar. Just like our skin, our brain can also scar.

Astrocytes: More than Glue

astrosandneurons

Astrocytes (green) and neurons (red) imaged from the visual cortex of a mouse. In blue, cell nuclei. Image credit: Elena Blanco-Suárez.

In more recent years, researchers realized that astrocytes were doing more than just keeping the brain neat and building scars. In fact, they found that astrocytes have a very active role in helping neurons to create and develop their connections, called synapses.

Astrocytes make and secrete a bunch of proteins that are sent to neurons, like instructions. Dr. Ben Barres was a pioneer investigating the roles of these  proteins, or factors if you prefer.

For example, thrombospondins and hevin are some of those factors that are made and secreted by astrocytes, to promote the structural formation of synapses. However, those synapses are “silent”, due to lack of AMPA receptors (AMPARs). The postsynaptic neuron (the receiver) needs those particular receptors to properly catch signals (neurotransmitters) coming from the presynaptic neuron (the sender) in order to transmit the nervous impulse along to the next neuron.

Synapses go through different stages of development, maturation and stabilization, and it was unclear whether astrocytes had roles further than structural formation of synapses. But now we know that astrocytes have the key to drive those receptors to the surface of the postsynaptic neuron.

Once the structure of the synapse is in place, AMPA receptors (AMPARs), the main transducers of the excitatory nervous signal, will be recruited thanks to other astrocyte-secreted factors, proteins like Glypican 4 and 6.Glypican 4 and 6, however, recruit a specific type of AMPARs, those that lack the subunit GluA2. AMPARs are made of 2+2 subunits, that range from GluA1 to GluA4. The subunit composition is characteristic of age, or the brain region considered, for example.

AMPAR

AMPAR are heterotetramers. The receptors are composed of 4 subunits, and its composition depends on the brain region, and age. For instance, in the adult hippocampus, the most common AMPAR composition is 2 GluA2 subunits and 2 GluA1 or 2 GluA3 subunits. Credit: Elena Blanco-Suárez.

In early stages of development, AMPARs usually lack the GluA2 subunit. This makes the synapses immature so that they are able to adapt and build brain circuits based on the experiences that the brain is exposed to. This ability is called plasticity. The older we get, the less plasticity the brain shows. Brain circuits show high plasticity at specific time windows during development, called critical periods. This is partially the reason for why learning a language seems harder at an older age, compared to kids who seem to be able to learn any language effortlessly. Accent and all.

critical periods

Critical periods for humans. Senses develop their circuits early in life, whereas the high plasticity for language acquisition comes a bit later. The latest critical period is for higher cognition such as mathematics, critical thinking, reading, etc… Adapted from Jon Bardin. Neurodevelopment: Unlocking the Brain.  Nature News Feature, 2012.

Since we saw astrocytes were in charge of the structural formation of synapses, and the insertion of AMPARs to make silent synapses functional in early development, we asked: Do astrocytes also promote maturation of synapses?

As we get older, the synapses mature, and this maturation comes with replacing GluA2-lacking AMPARs for GluA2-containing AMPARs. As it turns out, my own research showed that another astrocyte-secreted factor, called Chordin-like 1 (Chrdl1) can indeed promote the replacement of those GluA2-lacking AMPARs with GluA2-containing AMPARs, as well as promoting the formation of new and functional synapses.

This proves that astrocytes’ role goes beyond what was originally believed to be their functions of housekeeping and mere structural support. Now we know that they can regulate synaptic maturation.

Astrocytes’ Job is a Lifelong Endeavor

The astrocytic role in synaptic maturation suggested that they would also have a say in the brain’s plasticity, since the more mature the neurons are, the less plasticity is displayed. Our circuits need to settle, as they can’t (and shouldn’t) stay immature for our entire lives. Though it may sound appealing to keep your brain highly plastic, able to adapt easily, and potentially learn effortlessly, think again. Would you want to keep your brain in the state that it used to be in when you were a child, at the peak of its plasticity? Not necessarily, as it is probably in your best interest to develop fully functional brain circuits.

But would there be a way of making the adult brain as plastic as a 5-year-old at a precise moment? For instance, at older ages the outcome from a stroke is not so favorable due to declining plasticity. Could we then summon astrocytes to promote plasticity? Could we fool our own brain to make it as plastic as it needs to rebuild broken circuits?

I saw that the effect of astrocytes in brain plasticity was not restricted to critical periods, but was also apparent in adults, when the circuits are allegedly stable and less plastic. Manipulation of astrocyte-secreted factors hold promise to be able to aid and boost the brain’s own ability to repair itself in the event of a stroke, a traumatic brain injury, or any other disorder that may depend on plasticity.

Then, why don’t astrocytes always? go to the rescue naturally?

Because when we get older, our astrocytes also suffer. In fact, due to different changes that come with age, astrocytes turn from friends to foes. For example, they start eliminating synapses that otherwise would be needed, and they decrease their cholesterol production which is absolutely necessary for the brain to keep its health.

Unraveling the mechanisms by which astrocyte-secreted factors can form, develop, and mature synapses will shed light on why later in life, they become lazy in their outstanding mission. Knowing this could help figure out how to use the power of astrocytes to regulate plasticity  to benefit the older brain.

 

References

Allen NJ, Bennett ML, Foo LC,Wang GX, Chakraborty C, et al. 2012. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486:410–14

Bartheld, C. S., Bahney, J. and Herculano‐Houzel, S. 2016, The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting. J. Comp. Neurol., 524: 3865-3895. doi:10.1002/cne.24040

Blanco-Suarez E, Liu TF, Kopelevich A, Allen NJ. Astrocyte-Secreted Chordin-like 1 Drives Synapse Maturation and Limits Plasticity by Increasing Synaptic GluA2 AMPA Receptors. Neuron. 2018 Dec 5;100(5):1116-1132.e13. doi: 10.1016/j.neuron.2018.09.043. Epub 2018 Oct 18.

Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ. The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain.  Cell Rep. 2018 Jan 2;22(1):269-285. doi: 10.1016/j.celrep.2017.12.039.

Christopherson K, Ullian E, Stokes C, Mullowney C, Hell J, et al. 2005. Thrombospondins are astrocytesecreted proteins that promote CNS synaptogenesis. Cell 120:421–33

Kucukdereli H, Allen NJ, Lee AT, Feng A, Ozlu MI, et al. 2011. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc. Natl. Acad. Sci. USA 108:E440–E49

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