Unknown, unloved. It seems to be the life story of the glial cells, the ‘other’ cells in the nervous system. A growing number of recent studies show a far more important role for the glial cells than just supporting neurones. It may in fact be the glia – and one glial cell in particular, named astrocyte – that are the driving force in the nervous system.
German pathologist Rudolf Virchow discovered the glial cell in 1856 while searching for connective tissue in the brain. In comparison to the dazzling neurone with its beautiful structure and interesting activity the glial cell seemed rather dull. A small, stubby cell quite inactive and without a clear task. Even its name, derived from the Greek word for glue- or even worse – slime, suggests depreciation.
For many decades, research of the nervous system has been focused on neurones despite the fact that glial cells far outnumber neurones. Unlike neurones, glia lack the long and short sprouts called axons and dendrites. But this doesn’t prevent them from communicating, orchestrating, managing, and fulfilling a wide array of tasks.
“Glial cells are critical participants in every major aspect of brain development, function, and disease”, says Ben Barres, neurobiologist at Stanford University. “Far more active than once thought, glial cells powerfully control synapse formation, function, and blood flow. They secrete many substances whose roles are not understood, and they are central players in injury and disease in the central nervous system.”
Astrocytes are the most numerous glial cells. Their name, originating from the Greek word for star ‘astron’, comes from their thought to be star-shaped cell body. A new staining method, though, revealed their true form. The overall outlines of astrocytes are far from star-like. They are cubic or rounded, are highly fibrous, have great structural complexity and a dense array of processes (outgrowths).
Some of the astrocytes long processes terminate in end-feet. These touch the surfaces of neurones, possibly to bring nutrients. They also touch blood vessels to form the tight junctions necessary for the blood-brain barrier that prevents toxic substances in the blood from entering the brain.
Other important tasks known so far include removing debris after injury or neuronal death, fulfilling housekeeping chores such as taking up released neurotransmitters. They seem to have a huge influence on synapses, the connections between neurones. By modifying the strength of these connections, astrocytes play a role in learning and memory.
The distribution of astrocytes throughout the central nervous system is highly organised. Collectively, these astrocytes form a kind of matrix in our brain. Every astrocyte controls and manages its own little piece of brain, including neurones and neurotransmitters present. They seem to control the birth, the development, the functional activity, and the death of neuronal circuits.
Although many neuroscience textbooks still claim the opposite, more and more evidence emerges that astrocytes are not only able to listen to but are also capable of talking back to and instructing neurones. Astrocytes communicate with each other, with other glia, and with neurones. Calcium is their main tool for communication.
Astrocytes have receptors for a wide variety of neurotransmitters and can release many neuroactive substances. The function of this signalling is still unknown as is the way this alternative mode of communication within the nervous system affects higher brain processes. There are indications that astrocytes help control the development and function of synapses. In a laboratory setting, neurones co-cultured with astrocytes develop seven times more synapses and experience an increase in synaptic efficacy compared to neurones raised without astrocytes.
Astrocytes also play a major role in disease. Through their control of critical neurotransmitters such as glutamate they appear to be involved in psychiatric disorders as anxiety and schizophrenia, but also in neurodegenerative disorders as Parkinson’s disease and motor neurone disease (ALS). Damaged astrocytes may play a role in triggering epileptic seizures and in chronic pain. There might even be a link between the loss of astrocytes and depression.
An exciting new finding is that adult stem cells in fact are astrocytes. They can develop into ordinary astrocytes, but can also become neurones. So instead of being the servants, astrocytes are more likely the parents of neurones. And what we call neurogenesis should in fact be named gliogenesis. Astrocytes constantly divide in the brain throughout adulthood. When we learn, they increase the division pace and in the hippocampus, the brain part important in learning and memory, every now and again become neurones.
When the constant turnover of astrocytes is disrupted, problems arise. The growth and elimination of synapses depends on the growth and health of astrocytes. It seems they are in higher demand in neurodegenerative diseases. Stem cells injected in mice with Alzheimer disease like symptoms in overwhelming majority turn into glial cells and not into neurones.
It is likely age-related decline and degenerative brain diseases occur because astrocytes for some reason don’t do their job properly. Sustaining an adequate astrocyte turnover thus would lead to a healthy brain. It should be investigated how we can stimulate such a healthy astrocyte growth. This will be a daunting task as excessive growth of astrocytes results in brain tumors (60 to 70 percent of brain tumors are of astrocyte origin).
“Quite possibly saving astrocytes from dying in neurobiological disease would be a far more effective strategy than trying to save neurones. Glia already know how to save neurones, whereas neuroscientists still have no clue”, says Barres.
Glial cell champion and neuroscientist Maiken Nedergaard, then at Rochester University New York and now at University of Copenhagen, Denmark, says: “These heretical ideas, based on in-depth studies, drastically reshape how one thinks about brain function. And of course, they have implications for how function could go awry. Let us be clear about one thing: we are still in the early stages of understanding how these findings fit together with conventional neurone-oriented doctrine. Other facts about astrocyte behaviour and organisation might help in thinking about possible ways forward.”
Or, as Barres puts it, the most important roles of glia have yet to be imagined.
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