Saturday, 15 November 2014

Meet the cells that keep neurons running

by Jonathan Smith

When watching a Formula 1 race, it’s easy to forget that the racing drivers, skilled as they are, don’t work alone. When the car pulls into a pit stop, however, you see a bustling team of mechanics and other experts eagerly rush out to keep the car and driver in top condition. Meanwhile, security staff stand by, blocking public access and keeping a watchful eye on any danger that may present itself. Similarly too, the F1 drivers of the nervous system, neurons, get a lot of attention due to their unique information-processing properties. However, there’s a diverse team of specialised cells that beaver away in the background of the nervous system, carrying out essential tasks analogous to the F1 driver’s pit stop team. Without these plucky little cells, neurons wouldn’t propagate information properly and the nervous system would cease to function. With that in mind then, let’s give some of the most important overlooked cells the limelight for a change, starting with the ‘security guards’ of the mammalian nervous system.

Endothelial cells form the Great Wall of the Brain
As we eat, sleep and move about, our blood ion and sugar levels are constantly in fluctuation. For our neurons that require tightly controlled conditions, exposure to this would be highly detrimental. Thankfully, we can look to endothelial cells, which line the interface between brain tissue and the bloodstream, forming a shield against peripheral influence known as the Blood-Brain Barrier (BBB). By surrounding blood vessels and plugging gaps in the line with protein complexes called Tight Junctions, these endothelial cells and their buddies the pericytes not only cushion brain tissue from fluctuating ion and glucose concentrations but also block passage to many complex molecules, including foreign pathogens.

Figure 1: The endothelial Blood-Brain Barrier around a capillary (red chamber) combines with glial cells such as microglia and astrocytes to form a safe nutrient delivery system to neurons. Pericytes and tight junctions help the endothelial cells to seal the boundary and astrocytes use an end foot process to suck up the nutrients passed along by the barrier. Microglia wait on the side, checking for hazards. Source: SR Yusof and NJ Abbott, from Abbot, 2013, doi: 10.1007/s10545-013-9608-0

Not content to simply act as a wall, these cells also tirelessly shuttle essential ions, sugars and other chemicals into the brain and remove toxins through their own cytoplasm, ensuring that neurons are both protected from the outside world and aptly supplied with the nutrients they require. Furthermore, white blood cells of the immune system - the body’s police force - regularly squeeze through the barrier in order to check for danger. However, this also works against the brain in conditions such as strokes in which the BBB becomes leaky and can’t limit the passage of white blood cells, thus increasing inflammation and exacerbating the problem.

You won’t like microglia when they’re angry
Inside the BBB we encounter the glial cell population. Glial cells - named after the Greek word for ‘glue’ - share many characteristics with neurons but lack the unique structures and functions that specialise neurons for information transmission. Instead, glial cells play a diverse set of roles maintaining the nervous system. Numbering at around 15% of all glial cells, security guard microglia are the subject of intense research because of their incredible versatility. These cells spend the majority of their time simply sitting in the brain tissue, waving their dainty branch-like processes around in a constant search for signs of danger. When they pick up a scent of damage or invasion, however, microglia turn ugly. These sentinels kick off tissue inflammation and undergo an Incredible Hulk-esque transformation into a blob that engulfs and digests the offending party before innocently reverting back to its original state. 

Figure 2: Microglia (green) detects a tissue injury and springs to action. Its extended processes detect signs of damage and trigger the cell’s transformation into a big blob that engulfs the debris. Source: adapted from Nayak et al, 2014, doi: 10.1146/annurev-immunol-032713-120240

With this astounding response to hazards, microglia make impressive enforcers. However, mountains of research have revealed that they can do much more than this. They communicate with cells of the immune system that pop in every so often. In addition, microglia have been found to nurture the growth of neurons in embryonic development and help to prune unwanted cells from the nervous system in developing juveniles. They could even play an important role in synaptic function, making them crucial for normal information processing. However, these eager cells may also work against us in neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease, believed to involve high inflammation that proves to be neurotoxic in the long run. By better understanding the role these cells play in the pathology, we might able to devise new strategies for treating these conditions.

Insulating the wiring with oligodendrocytes
Mammal neurons are small, thin cells compared to some of the whoppers found in invertebrate animals such as the giant squid. Most neurons output their information through a long process called an axon and, due to electrical resistance inside the cell, neurons with thinner axons propagate information more slowly than those with thicker axons. How then could a nervous system operate with such small neurons? The answer is myelination. This is the process by which specialised glial cells called oligodendrocytes and their peripheral cousins Schwann cells tightly wrap their own fatty membrane - the myelin sheath - around the axons, leaving little gaps of axonal membrane that allow electrical potentials to ‘jump’ significant distances along the axon. This increases possible propagation speeds up to 100 metres per second in humans - perfect for neuronal communication.

Figure 3: Oligodendrocytes (blue) ensheathe many axons (brown) in myelin to facilitate electrical transmission. Source: Wikipedia

Insulation might not be the only function for these ‘mechanics’ of the nervous system. Recent research indicates that oligodendrocytes can not only insulate axons, but may also directly support the axon’s energy requirements by supplying substrate molecules used in metabolic reactions such as lactate. Further studies indicate that oligodendrocytes promote neuronal survival and axonal growth. The importance of these cells and Schwann cells is further underscored by the fact that the disorder Multiple Sclerosis (MS) arises from demyelination of axons throughout the nervous system. For a multitude of reasons, the immune system attacks myelin and thus deprives neurons of essential support, causing neurodegeneration and, as a consequence of this, ultimately life-threatening paralysis in MS patients. However, strategies are now being trialled that may be able to divert or retrain the immune system and prevent the progression of MS.

Astrocytes - star players in the nervous system
Astrocytes are star-shaped glial cells thanks to their many fine processes, hence the name. Acclaimed as the most abundant type of cell in the human brain, these cells have the chief responsibility of transporting nutrients from blood vessels to nearby neurons by means of a long ‘foot’ process. Astrocytes also oversee chemical synapses - vital junctions at which neurons communicate using neurotransmitters - and each astrocyte can monitor up to a whopping 140,000 synapses! Taking roles analogous to trainers, medics and mechanics in the F1 team, astrocytes are absolutely essential for the survival of the nervous system and by extension, the entire organism.

As can be expected, lots of research gets devoted to unraveling the precise roles that astrocytes play in the nervous system. It’s now clear that these ubiquitous cells encourage the formation and pruning of synapses in the developing brain. In addition, they fine-tune synaptic activity by supplying necessary energy substrates, hoovering up and recycling excess neurotransmitters, prevent seizures by clearing away potassium ions and physically ensheath the synaptic space, reducing spillover of neurotransmitters to nearby cells. Unfortunately, astrocytomas are among the most common cancers in the nervous system and have a relatively high mortality rate. They damage the brain tissue by increasing pressure inside the skull, compete for nutrients and releasing toxic chemicals into the brain, resulting in varied symptoms including headaches, seizures and occasionally personality changes. Though the classic cancer treatments are available such as surgical removal, it’s hard to cut away all of the high-grade tumours due to their rapid infiltration into the brain.

Collective thinking
Aside from the heroes discussed in this piece, there are also tons more subsets of cells that deserve honourable mentions, including parenchymal cells that circulate cerebrospinal fluid around the brain and the somewhat enigmatic NG2 glia, whose precise function still eludes us. While staying mostly in the background, these other cells all have vital functions that serve to ensure that our neurons keep running smoothly. 

Neurons tend to be the main focus of neuroscientific studies. This attention is well deserved considering that they are the substrates of our very thoughts. However, after examining some non-neuronal cells, it’s clear that neurons wouldn’t last a minute without the help of their expert team on hand. By exerting modulatory influence on neuronal development and synaptic activity, it could be argued that the support cells similarly affect our thinking and learning processes, an argument particularly evidenced by complex neurodegenerative diseases involving lots of cell pathologies. With this in mind then, let’s all watch some F1 and spare a thought about the collaborative efforts involved in securing first place!