A journey through glia and some other astroplaces
The human central nervous system, the brain and spinal cord, are made up of two types of cells; neurons and glia. Neurons are the fundamental building block of the nervous system; transmitting information electronically and chemically through a complex network of connections. Neurons are intrinsically linked to the study of brain function that they lend their name to the entire field. Their functions are highly diverse, often seemingly miraculous and will not be mentioned again for (almost) the remainder of this paper. We are here to explore the glial cells, the glue that makes up around 90% of the mass of your central nervous system but receives far less of the credit. This exploration should not be taken as a competition between the neuron and the glial cell. Both are absolutely crucial and this kind of argument would be about as productive as debating whether lungs or blood are more crucial to getting oxygen to your body. Rather, it is an effort to get you thinking about what glia do and how they fit into our neuron-centric world. In short, is there room in neuroscience for glia?
The term glia has the same derivation as the world glue; this is not accidental. They were so named by anatomists in the 1800’s when brain dissections revealed two distinct cell types; the thin radiating neurons and the thickly webbed glia, far more prevalent. Structural support is certainly an important role of glia but it is far from the only one. Glia is actually an umbrella term used to describe many different types of cells within the central nervous system, however there are three major varieties that will be the focus of our present inquiry: oligodentrocytes, microglia and astrocytes.
Oligodendrocytes are the myelin producing cells of the central nervous system. Myelin is the fatty compound that wraps the axons of vertebrates. Myelin serves several crucial functions including insulating nerve tracts and allowing for far faster transmission of a nerve impulse than would be possible in an un-myelinated cell. This speed-up occurs through a process called saltatory conduction in which an action potential jumps from one crease in the myelin to the next (these creases are called nodes of Ranvier). Interestingly, oligodendrocytes do not secrete myelin onto nerve cells but instead wrap long cell-body extensions around several axons. These long projections are actually myelin. Myelin should not be thought of as an insulating sheath, instead picture lots of many-armed men reaching out and grabbing lots of nearby axons. Now keep adding many-armed men until every axon is completely covered and you have a more realistic image of oligodendrocytes.
Microglia are the immune cells of the central nervous system, period. The body’s usual alphabet soup of infection-fighting immune system cells cannot cross the blood-brain barrier and do not enter the central nervous system under normal conditions. Some sneaky infections do make it across the barrier however and it’s up to microglia to destroy them. It’s not easy to get an immune cell into the central nervous system and unlike normal immune cells which only last a short time (besides memory cells) microglia survive for many years. The existing cells also multiply in situ to increase their numbers, another microglia-only trick. Early on, a few precursor immune cells called monocytes made their way into the developing central nervous system. They set up shop and began dividing into the various kinds of microglia. Why various kinds? Because microglia have to perform the role of every single immune system cell all by themselves! They phagocytize and present antigens like the hardiest macrophage and coordinate the cytotoxic response like a T-cell…at the same time. Perhaps their greatest trick however is their ability to down-regulate into an immunologically silent state in order to provide the brain with the “clean slate” it needs for efficient neurotransmitter messaging. Microglia remain in an inactive state, some anchored in critical locations and others floating freely in the cerebrospinal fluid just watching and waiting for some chemical sign of cellular distress. When a signal is received they leap into action, rapidly activating, multiplying and diversifying until they can mount a complete immune response.
While the incredible variability and plasticity of the microglia is certainly a hard act to follow, the final type of glial cell we will explore today, the Astrocyte can certainly hold its own. Astrocytes are so named because they resemble stars with a central body radiating many cytoplasmic extensions outward in all directions. These were the cells whose structure gave rise to the original term of glia and as their form would suggest structural support is one of their roles. However if you could peer inside a brain you would notice that the astrocytes extensions do not simply reach out at random but instead always grab blood vessels or synapses. These two locations provide hints about two highly important functions of Astrocytes. The first is the formation of the blood-brain barrier.
The blood-brain barrier is a very well known concept, often taught all the way back in introductory biology. We all know that most compounds carried in blood, from drugs to immune cells to pathogens cannot cross into the brain. What is far less known is how the unique physical structure of astrocytes is responsible for this process. Like oligodendrocytes and axons, the cellular extensions from astrocytes surround each and every capillary in the brain. This astrocyte “seal”, coupled with many tight junctions, is the blood-brain barrier…but now for the better question…if every blood vessel is totally wrapped in astrocytes, how do the neurons get any oxygen? The answer is that the astrocytes bring the oxygen to neurons exactly when they require it. If this seems like a surprisingly complex function for a basic “structurally supportive cell” get used to it, it only gets better from here. Chances are you already know a lot more about the process by which astrocytes bring oxygen to neurons than you even realized. Every time you see an fMRI image purporting to show neuronal activity what you are really seeing is a highly accurate map of astrocyte activation. When a neuron is active it releases chemical signals which cause the astrocyte to uptake oxygen from its nearby capillary and transport it to the needy neuron. Thus what the fMRI is measuring is how active each astrocyte is, the inherent assumption is that astrocyte activations is fully dependent on neuronal activations. While there is certiabnly some truth to this linkage as we further explore astrocytes it may encourage fMRI results to be viewed with a bit more skepticism. At the very least these findings reduce the spatial and temporal accuracy of fMRI as one astrocyte may supply a number of neurons and takes a bit of time to actually respond to increased activity.
Now that we understand why astrocytes grab blood vessels it is time to look at what, for me at least, is the most interesting role of astrocytes: their involvement in synaptic transmission. Recent research has suggested that astrocytes do not just have extensions that sometimes meet synapses rather that every synapse always features an astrocyte extension that is absolutely critical to its proper function. Originally the astrocytes role at the synapse was thought to be passive in nature; the astrocyte supposedly insulated the synapse and increased the efficiency of neurotransmitter action. While this may be true it is only the beginning of the story. Astrocytes respond to changes in neurotransmitter levels by releasing their own neurotransmitters. Furthermore astrocytes play a major role in the re-uptake and breakdown of neurotransmitters within the synapse. Recently, researchers have suggested the idea of a “tripartite synapse”; this terminology suggests that there are three players in every synapse: the pre-synaptic membrane, the post-synaptic membrane and the astrocyte. Thus the astrocyte is elevated to a level of importance within the synapse equal to that of the neuron.
Astrocytes do not merely assist with neuronal messaging however. A great deal of contemporary research has focused on signally from astrocyte to astrocyte without any help from the neuronal network. This signally generally takes the form of calcium ion release which spreads rapidly along the extensions of an astrocyte. It spreads from astrocyte to astrocyte through small cytoplasmic links called gap junctions that can be thought of as a porthole linking two astrocytes. These calcium waves can activate distant astrocytes and even cause of the release of other neurotransmitters such as glutamate. If the idea of a an entire parallel network of signal exchange in the brain is a bit shocking, you are not alone. A great deal remains to be learned about what information is actually carried by the astrocyte network and is perhaps the greatest question that the study of glia has proposed so far.
Now that we have taken a closer look at several kinds of glia it is time to return to our original query; where do these cells fit into the study of neuroscience? The first two cell types we explored; oligodendrocytes and microglia are easier to evaluate as their roles are supportive in nature. When oligodendrocytes are working properly they simply help the neuronal network do its job, they only become important when they fail to work properly such as in the case of multiple sclerosis, a demyelinating disorder. Microglia are really highly modified immune cells and most inquiry into their function tends to view them as such. They have little to do with information exchange and a great deal of microglial activation is usually a very bad thing for efficient neuronal function. These cells are clearly important factors in neuroscience however their lack of involvement in neuronal activity also seems to preclude them from fitting under this label. Instead I propose a new umbrella term to cover their study: “brain biology”. We have allowed neuroscience to become the study of the brain as it relates to the mind; however there is a clear need to continue studying the non-processing aspects of the brain and a term like brain biology would encompass these areas of study without sullying the sexy connotations of neuroscience.
The real question from all this philosophy is where do astrocytes fit into the picture? They clearly exchange information so should they be in neuroscience? However on the other side of the coin, astrocytes’ functions are highly supportive and the nature of the information that they carry is not well understood and may simply reflect excitatory or inhibitory messages regarding neuronal activity so should they instead be in brain biology? I would expect an astrocyte researcher would passionately argue for inclusion in neuroscience but this is neither surprising nor particularly enlightening. Astrocyte research represents a new branch of neuroscience where the questions vastly outnumber the knowledge. This potential goldmine of novel and publishable findings attracts young, ambitious researchers who receive an increasing number of research grants. Some in the more established community feel that the excitement over glia is overblown and that their functional findings do not begin to approach anything seen in neurons. They feel that while glia are certainly crucial to proper neuronal function their supportive role affords them the same place offered to the diaphragm in pulmonary research; certainly critical, very involved but not really what we are trying to talk about. The only way to this question can be answered is through further research. It is the burden of the glial researchers to prove their worthiness for a place in neuroscience but what is the obligation of the current neuronal researcher? Their desire to focus on the better understood aspects of neuronal function must be balanced with a need to provide the next generation of students the tools to understand this new branch of research. Ultimately I feel that glial cells should be a part of a basic neuroscience curriculum…a well rounded student should be familiar with the concept and prepared to critically analyze any future research in the field.