Glial cells have been regarded for years as the poor, red-headed step child to neurons in the brain. It has generally been considered that glial cells serve as support structures for neurons. The general analogy used relates glial cells to be the “glue” that holds neurons together. Glial cells perform many important (if mundane) tasks such as mopping up excess ions and recycling neurotransmiters. Glial cells also provide physical support for neurons, guide axon/dendrite growth, maintain a stable cocktail of chemicals in the fluid surrounding the brain and coat axons in myelin.

Glia, however, has always been assumed to take a backseat when the “real” work of the brain happened, watching from the sidelines as the flashy neurons communicated with eachother. Recent research may finally bring glial cells off the sideline and give them some credit they deserve. More details after the jump.

…These data indicate that glia contribute actively to the transfer and storage of information in the central nervous system. The findings reviewed above, however, are only beginning to scratch the surface of what will be an explosion of findings related to glial modulation of brain function

Synaptic plasticity is all the rage right now. Many people are focusing on what is happening inside the synapses. This review, however, looks at what is happening around the synapse. Astrocytes, the most common glial cell, physically encompasses nearly 60% of the synapse that connects two neurons. Such an arrangement begs further study to determine if astrocytes play any part in synaptic transmission.

Research has been looking at at NMDA Receptors (NMDARs) in pre- and post-synaptic neurons. NMDARs are often implicated in synaptic plasticity. Given a sufficiently large enough increase in Ca²⁺ and activation of NMDARs, various pathways are triggered which add or remove AMPA Receptors (AMPARs) to the surface of the synapse. Therefore, NMDARs act as great coincidence detectors. When a neuron is firing and its NMDA receptors are being activated the neuron is aware (for lack of a better term) that the neuron is being stimulated at this synapse. Pathways are triggered and the synaptic transmission is either strengthened or weakened by the addition/removal of AMPARs.

“What does this have to do with glial cells!” you demand? D-Serine is a NMDAR agonist, a rather potent one at that. And it just so happens astrocytes are highly enriched in D-Serine. When you combine these three properties (potent agonist, physical location of astrocytes around synapses and NMDARs’ role in synaptic plasticity) it just begs to ask the question “Perhaps glial cells help mediate synaptic plasticity”. It would be easily conceivable that plasticity requires three parties instead of two, as originally believed.

That said, researchers admit the presence of D-Serine in astrocytes does not conclusively confirm glial cells involvement with synaptic plasticity. It is possible the high concentration is the result of neurotransmitter recycling and does not play an active role. If glial cells are indeed manufacturing D-Serine for the purpose of synaptic plasticity, it is still unknown if they have the capability to release it into the synaptic cleft. The paper does mention an earlier experiment where NMDAR regulation by D-Serine only occurred when the neurons were co-cultured with glial cells. When neurons were cultured by themselves, this regulation did not occur, suggesting that glial cells play a critical role.

An interesting property of astrocytes is their physical relationship to neurons. Astrocytes are very physically plastic, capable of drastically changing their shape. Importantly, these changes are often reversible. For instance, the introduction of oxytocin into the brain drastically reduces the coverage of astrocytes on oxytocin-producing neurons. And as astrocyte coverage receded, so did the activity of NMDAR mediated pathways in oxytocin-producing neurons. This highly suggests that a gliotransmitter (chemical transmitter released from a glial cell, instead of a neuron) is involved. The effect can be completely reversed by introducing a saturated solution of D-Serine.

Other gliotransmitters include TNF-α and ATP. TNF-α , for instance, increases the expression of AMPAR on the surface of the neuron. It is believed that AMPARs help moderate homeostatic plasticity. Homeostatic plasticity is a neurons response to chronic increase or decrease of a synapse strength over long periods of time. For example, if a synapse is getting chronically weaker, increasing the expression of AMPAR makes the neuron more sensitive to the weaker signal. Conversely, decreasing the expression helps keep chronically strenghtening signals from getting “too loud”. TNF-α can be secreted by neurons but the evidence strongly supports a glial cell origin. Further research is needed to study glial cell’s role in TNF-α production and secretion

The data presented is a tantalizing look at glial cells and a more active role they might play. Research is on the cusp of connecting the two. Currently, research has only uncovered possibilities, various transmitters and coincidences that highly suggest glial intervention. If glial cells are indeed involved, this could be a huge breakthrough, given glial cells’ physical proximity. There is also a wide array of glial cell types, as well as inter-glial cell communication. Taken together, it appears that glial cells could be vastly more important than simple “glue” to support neurons.

J. Bains, S. Oliet. 2007. Glia: they make your memories stick!. Trends in Neuroscience 30.8: 417-424

doi:10.1016/j.tins.2007.06.007