The Roles of Astrocytes and Oligodendrocytes

This is a follow-up to my previous article wherein the neurogenesis of neurones in hippocampus was briefly described. For making a better view on this, I summarise a few characteristics of other cell types, which are derived from neural progenitor cells.

Neural progenitor cells that did not develop into neurones can become glioblasts, which are precursors of astrocytes or oligodendrocytes. These two types of cells are quite different morphologically and functionally; a common factor between the two is primarily to help neurones to function, and to facilitate neurotransmissions.

Astrocytes support neuronal survival and synaptic transmissions

Astrocytes are relatively large cells with sponge-like appearance, extending multiple dendritic protrusions which display finely intricate branching patterns. Astrocytes can be found between blood vessels and neurones, or by synapses.

Basic Role 1: Astrocytes As a Crucial Supplier to Neurones

At blood vessels, astrocytes participate in forming the blood-brain barrier, which selectively takes necessary substances from the circulation into the brain. It sieves out larger and charged molecules sufficiently, but lipophilic substances (e.g. alcohol, synthetic lipid-soluble compounds) that permeate through the cell membranes cannot be excluded by this mechanism; hence such substances elicit central effects.

The blood also carries glutamate, an excitatory neurotransmitter, to the brain. In order to avoid neurones to get excited unnecessarily, neurones do not make a direct contact with the blood vessels. Astrocytes can collect glutamate via glutamate transporters (EAAT1-3) and convert that to a less excitable glutamine.

Glucose, the energy source, is also carried in the blood. Astrocytes collect glucose from the blood using their glucose transporter (GLUT1), and give much of that to energy-intensive neurones after converting it to lactate, which is readily utilisable in ATP synthesis.

Basic Role 2: The Synapses Are Protected by Astrocytes

At synapses, glutamate needs to be removed soon after the transmission, for not only a prolonged excitation cause seizures and paralysis by hyper-activating neurones, an excessive excitation could destroy neurones. The availability of glutamate at synapses therefore needs a close monitoring: astrocytes do this by collecting excess glutamate.

Q&A: G-Protein Couple Receptors and Calcium Oscillation in Astrocytes

The roles of astrocytes mentioned above are important for neurones to function, but the story does not stop there. Astrocytes in fact express various receptors for neurotransmitters including: adenosine triphosphate (ATP), serotonin (5-HT), acetylcholine (ACh), noradrenaline, histamine, dopamine and glutamate. Why do astrocytes have them, and what are they for? These receptors (GPCRs) raise intracellular calcium concentration by releasing calcium stored within the cells.

Then, do astrocytes release transmitters via synaptic vesicles like neurones, responding to the raised intracellular calcium concentration?

- They do, though such events may not be as major as in neurones; they don’t seem to have an obvious active zone at which dense vesicles accumulate as typically seen in the terminal of pre-synaptic neurones.

- They certainly do: there have been several evidences (1) indicating astrocytes release glutamate in calcium-dependent manner.

Release to where? How would that be useful?

- Astrocytes and neurones are known to form altogether a tripartite synapse comprising pre- and post-synaptic neurones, and peri-synaptic astrocytes. Astrocytes thereto release “gliotransmitter” in support of neurones, as well as protecting them by collecting excess excitatory neurotransmitters.

What on earth is gliotransmitter?

- In the tripartite synapse, astrocytes respond to presynaptic neurones, and release transmitters including glutamate, ATP, prostaglandin E2, and D-serine, in facilitating neuronal activity and synaptic transmission. The term gliotransmitter is used to distinguish the cellular origin of these chemical transmitters at the synapse.

Right, pre-synaptic neurones send signals to astrocytes: is that why the astrocytes have various GPCRs for neurotransmitters?

- I should think so. There is an evidence that exogenous ATP or ACh can increase the astrocytes interconnecting, but not via glutamate (1). Let us move onto see how their interconnection is important, in the next subsection.

Q&A: Gap Junctions and Calcium Oscillation in Astrocytes

Astrocytes can communicate with neighbouring cells by exchanging chemical substances through small gaps between them, known as gap junction. Astrocytes send inter-cellular calcium signalling via gap junctions; by doing that, the signal of calcium oscillation can spread widely across the cells.

Yes, they say that calcium ions propagate waves inside cells and make oscillatory changes. Can you tell us what’s behind the oscillation with a few numbers?

- At resting conditions, intracellular calcium concentration is kept very low, about the ratio of 1:10,000 relative to the extracellular concentration. Upon stimulation, the intracellular concentration is raised by: the release of intracellular storage via certain GPCRs of which action opens IP3 receptors (IP3R) on the endoplasmic reticulum (ER) that stores calcium; and/or by calcium influx via ionotropic channels. The ER also has ryanodine receptor (RyR) which opens at higher calcium concentration. The intracellular calcium concentration is increased from ≈ 0.3 μM until it reaches about 1μM. The activity of phospholiapase C (PLC), which generates IP3, is up-regulated by calcium at its concentration over 100 nM; PLC also activates protein kinase C (PKC) that down regulates PLC. The numbers mentioned here refer to studies on smooth muscle cells (2). The phenomena is IMPOSSIBLE to be described satisfactory in a paragraph….

Let’s not neglect our subject, astrocytes. Is there anything identified to participate in mediating calcium waves in astrocytes?

- Astrocytes need to release ATP when propagating long-range calcium signals. PLC activation causes ATP release from astrocytes (3) and the released ATP to neighbouring cells activates their P2Y receptors (4) which activates PLC, and so it carries on. ATP is an important gliotransmitter between astrocytes through gap junction, as well as at the synaptic cleft between them and neurones.

Let’s carry on talking about another gliotransmitter.

- I’ll mention another one briefly in the next section, with a reference to learning process.

In Learning and Memories: Astrocytes facilitate neuronal transduction

Astrocytes can convert natural L-serine to unnatural D-serine, which is released as a gliotransmitter. D-serine increases calcium permeability of ionotropic glutamate NMDA receptors upon glutamate activation. As mentioned in my previous post (9th.Mar.11), young neurones start responding to glutamate excitatory signal via NMDA receptors with a pronounced responsiveness of long-term potentiation (LTP). These events initiated by calcium propagations do not readily cease, for various intracellular events leading to cellular changes and reorganisation are then processed; calcium signals are thereby crucial in synaptic plasticity, responsible in memory formation.



Oligodendrocytes increases the rate of neuronal conductances
The another type of glial cells, oligodendrocytes are large cells with several elongated protrusions, which can wrap around axon fibres to insulate them with regular intervals: this increases the late of axonal conductance enormously, as well as providing physical protection to the fine axon fibres. A single oligodendrocyte can wrap around (i.e. myelinate) separately each axon extended from a set of neurones that propagate simultaneously; this keeps the integrity of the neuronal activity as this allows neurones to be stay closer as a set of bundles. In this way, oligodendrocytes participate in maintaining coordinated brain networks.

It has been said that learning certain tasks, such as playing a musical instrument, could increase the thickness of the sheath extended from oligodendrocytes; but this might need more verification.

Recently, GPR17, which is a dual receptor for uracil nucleotides and cysteinyl-leukotrienes, was shown to be crucial in the maturation of myelinating oligodendrocytes, and the ligands to the receptor are potential regulators upon them under the normal condition and during myelin repair (5). Oligodendrocytes can also communicate with neurones by means of ATP (6).


Concluding remarks
Glial cells have been underestimated unsung heroes for a very long time. They deserve to be studied more.



R e f e r e n c e s

(1) Several research articles have been published over years by Dr. Philip G. Haydon and co-workers, regarding the function of metabotropic glutamate receptors in astrocytes.

(2) Summarised in a review article by Iino M, 2010. Spatiotemporal dynamics of Ca2+ signaling and its physiological roles. doi:10.2183/pjab.86.244.

(3) Wang Z, Haydon PG, Yeung ES. 2000. Direct observation of calcium-independent intercellular ATP signaling in astrocytes. Analytical Chemistry 72:2001–2007.

(4) Fam SR, Gallagher CJ, Salter MW. 2000. P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca(2+) wave propagation in dorsal spinal cord astrocytes. The Journal of Neuroscience 20:2800–2808.

(5) Fumagalli M. et al., 2011. J. Biol. Chem. http://www.jbc.org/cgi/doi/10.1074/jbc.M110.162867

(6) Please find several papers published by a group of Dr. R. Douglas Fields.



F u r t h e r R e a d i n g s

Neuroglia, 2nd Ed. Eds. Kettenmann H., Ransom B.R., Oxford Press. 2005.
A lovely book on my wish list. Expensive, but it definitely worths the cost. Beautiful.

The Root of Thought. Koob A. FT Press. 2009.
An affordable popular science book for casual read.