MICROGLIA—MASTER REGULATORS OF THE BRAIN
MICROGLIA ARE THE SMALLEST of the glia cells and are located throughout the brain and spinal cord. Essential to overall brain maintenance, they are related to immune scavenger cells, providing the main source of immune defense throughout the central nervous system.
But this is just the beginning of their amazing abilities. As both unique immune cells and vital brain cells that change shape depending on their environment, microglia have many different functions. Only recently has the complex life of microglia been able to be observed. We now know that they engage in conversations with neurons, astrocytes, myelin-producing cells, choroid lining cells, blood vessels, and immune cells.
A CELLULAR WORKHORSE
Neurons are masters of information transfer. Astrocytes provide nourishment, regulate blood flow, and perform synapse maintenance. Microglia travel throughout a defined brain territory observing, stimulating, inhibiting, cleaning up, fighting microbes, and maintaining all brain cells—while constantly communicating about brain activity.
As T cells are masters of the entire immune system, microglia are master regulators of all brain cells, including all immune responses in the brain. Microglia help determine how many brain cells of each type are needed in their various territories and signal to stem cells to produce more or fewer. In the fetus, microglia help establish neural networks. In adults, they signal for more connections. Signals nourish neurons when needed. Microglia participate in the migration of neurons and axons with directional messages in the fetus and early life.
Microglia with neurons. (GerryShaw/Wikimedia Commons)
Traveling independently in a small territory, they are not attached to any structure. Constantly surveying their particular region, microglia circle with extended arms that repeatedly touch everything—axons, synapses, astrocytes, myelin-producing cells, and extracellular matrix. Through contact, they determine suboptimal function. In addition, they communicate via complex wireless signaling to neurons and astrocytes, determining how many brains cells are needed and when to eliminate a synapse.
It is not known how microglia can determine the function of other cells by touching them. Recently, microglia were found to rapidly form an entirely new type of synapse when touching other cells. At this synapse, microglia are able to measure the concentration of molecules that are used to provide energy for cellular chemical reactions. This is one way they can determine if metabolism is suboptimal in a cell. Perhaps this new discovery will lead to an understanding as to how microglia utilize this information for their complex work.
Through constant surveillance, microglia find and eat microbe invaders, debris, and cancer and other damaged cells. With signals from other cells, they discover unwanted neuronal synapses and consume them. They find broken patches of myelin and signal for repairs. They participate in wide-ranging brain and immune conversations about stress.
Microglia originate in the yolk sac as scavenger white blood cells on the ninth day of fetal development. After traveling to the brain, they live their entire lives in a single small territory unless called to fight an infection or repair damage elsewhere. They reproduce in their region, creating a ready pool of additional microglia. They usually don’t produce new cells while circling and evaluating. These are generated during fights with invading microbes or while fixing damaged brain tissue. Most of the time, microglia behave as a stable dispersed community, each cell knowing its individual territory while talking with other microglia in different territories.
MANY DIFFERENT SHAPES
Because various microglia look quite different, only recently have scientists realized that multiple differently shaped cells that have been observed in the brain for years are really the same cell in different phases. No one understood that large bloblike scavengers are the same cell type as starlike moving cells that tap synapses. When microbe invaders appear, microglia morph into various shapes to fight them. Microglia start as small starlike mobile cells and rapidly become big round blobs. The blobs behave as activated immune cells that directly attack bacteria and viruses while signaling with other immune cells.
Another variant looks like an amoeba crawling along surfaces to find debris. A stationary type has many long, moving arms. A large granular type is filled with debris. While fighting infections, microglia can also form a uniquely shaped rod. Microglia next to blood vessels have less prominent arms while repairing blood vessels. Another quiet variety sits on the membrane barrier of blood vessels, waiting to help.
The amoeba-like shape was only recently observed, since it is difficult to detect the movement of a single cell in brain tissue. These use many long arms that can penetrate through astrocyte and neuronal networks. Arms that temporarily wrap around synapses and axons are constantly moving and tapping. Arms rapidly grow, shrink, and then regrow again.
In the brain, microglia are the most mobile and individualistic brain cell—functioning alone like a T cell with wireless communication to all other cells. Microglia normally don’t tread on each other’s territory, but when danger occurs, they swing into action and can go anywhere.
RESPONDING TO THREATS
Microglia respond to multiple threats in various ways. Via signals, they are immediately aware of problems in both local and distant brain regions. They can respond to different situations for minutes or for days. They are the only brain cells that are not physically connected to other cells and can rapidly travel and respond to cells signaling for help.
When damage in the brain occurs from infection or trauma, microglia are the first responders. They can present microbe particles to T cells by sending sacs that include the particle or even the microbe. Microglia then follow orders from the T cell. Microglia immediately start cleaning up any debris. They were first discovered crawling to an injury while eating dead microbes and damaged neurons along the way. Clearing rubble can make room for healing to occur. They can also send signals to suppress inflammation reactions in the brain.
Microglia are highly sensitive to signals from other immune cells, lining cells of the cerebrospinal fluid (discussed in chapter thirteen), and other supportive brain cells. They join in to investigate any unusual activity. With the slightest nerve injury, they suddenly become very active and change shape. Microglia are extremely active when there is any brain inflammation, including from HIV and other viruses; syphilis; cancer; neurodegenerative brain diseases, such as Alzheimer’s disease; and autoimmune diseases, such as multiple sclerosis. In multiple sclerosis, myelin is lost by autoimmune responses that include increased numbers of microglia as part of the inflammation. However, when myelin is being rebuilt, microglia can change their shape to help inhibit inflammation and trigger new myelin.
Like other immune cells, microglia respond to depression and emotional stress, such as social isolation. Stress increases microglia activity, and the number of microglia also increases in the brain regions related to stress—in the hypothalamus and pituitary. Microglia respond to pain as part of large multi-cell synapses discussed in chapter nine, about neurons, and chapter fourteen, about pain and inflammation. They send signals to coordinate higher-level emotional responses to pain.
If a large number of microglia are killed fighting microbes, reinforcements are required from subtypes of microglia that arise from bone marrow. These immune scavenger cells stay near the edge of blood vessels, ready to be called when original microglia are depleted. These substitute cells do not understand complex signaling in the brain like microglia that have grown up with other brain cells over a period of decades. These substitute cells gradually, over a period of eight months, accommodate to the brain, but never learn all of the functions of microglia.
MULTIPLE SIGNALS
Microglia use a wide range of signals and receptors while conversing with neurons, astrocytes, and immune cells. Microglia receive neurotransmitters from neurons and return signals altering neuronal activity. Signals to and from microglia include immune cytokines with travel directions for immune cells. Microglia send specific proteins that alter extracellular matrix for various purposes related to these other brain cells.
Neuronal signals affect microglia behavior related to inflammation and synapse pruning. Microglia learn new behaviors and signaling techniques from neurons. After years of brain experience, these signals make them superior to similar scavenger cells sent from bone marrow during immune crises. Microglia are the only cells in the brain with receptors responding to the cascade of molecules regulating blood clotting. They produce unique signals for each disease state, such as autoimmune diseases, trauma, and Alzheimer’s.
Like neurons, astrocytes, and cancer cells, microglia send messages using sacs filled with information molecules. Vesicles can be triggered by energy particles sent from astrocytes. One vesicle contains enzymes to cut proteins into pieces that each signal for inflammation. Others can contain immune signals for lymphocytes and receptors similar to those on T cells. They can include proteins necessary to fold receptors into their active shape. Another vesicle carries an enzyme related to opioid metabolism and pain. Some contain molecules related to Alzheimer’s.
Microglia vesicles can regulate neuronal activity by increasing axon firing and the number of neurotransmitters released at synapses. The previous chapter on astrocytes showed that lactate is sent by astrocytes for special energy use by neurons. Microglia also send vesicles to neurons with lactate for alternative energy.
RELATIONS WITH NEURONS
Microglia pay special attention to neurons. Under normal conditions, microglia send growth factors for neuronal health. They circle about eighty micrometers every few hours, examining every part of their territory, and use various tags to mark defective synapses for later elimination. Other synapses targeted for removal are identified by signals to microglia from neurons and astrocytes. Healthy neurons secrete signals to tell microglia not to eat their synapses. When neurons are desperate because of damage and infection, they trigger programmed suicide and signal microglia to clean up the debris.
Somehow, microglia know how many new neurons are needed in a fetus and later in life. They send messages to stem cells, along with other cells, to either produce or inhibit new neurons. Signals also stimulate new connections between neurons, especially in the hippocampus memory regions, where microglia are very active.
Microglia are critical during fetal brain development, when huge numbers of brain cells are produced. Their signals to stem cells determine cell production, rates of total brain growth, and the size of the fetal cortex. Rates are influenced by microglia eating excess stem cells. Regions producing the largest number of new neurons also have the most microglia. Near the end of pregnancy, the fetal brain produces hundreds of thousands of neurons each minute and then thousands of connections for each of these. Most connections aren’t used, and microglia eliminate them. Pruning molds brain connections, and eventually microglia become spaced into individual territories where they remain for life.
Microglia are critical for learning because they help rewire neuronal connections. Mice kept in the dark lose many synapses in eye centers and have large numbers of microglia there. When placed back in the light, new synapses appear and microglia move away. Microglia also signal for more myelin, which is vital for all learning, especially learning involving physical movements. Myelin is discussed in chapter twelve.
MICROGLIA IN DISEASE AND PAIN
Microglia play a critical role in brain diseases. Most of the time they are helpful, such as attempting to eat clumps of misfolded proteins in Alzheimer’s disease. But they can also prove harmful.
When inflammation is triggered, microglia can change into aggressive and destructive immune cells. They can damage synapses and release excessive neurotransmitters that increase the destruction. HIV-infected microglia release toxic material that damages neurons, contributing to HIV-related dementia. This also occurs in encephalitis from other viruses.
Microglia are fooled into transporting misfolded proteins around the brain. One abnormal protein is called a prion, which has been implicated in a number of neurodegenerative disorders in both humans and animals, including bovine spongiform encephalopathy, or mad cow disease. Prions stimulate increased numbers of microglia, and when microglia try to eat them, the microglia instead transport the prions to other regions.
Microglia also have been implicated in many types of pain. In neuropathic pain, neurons in the dorsal horn of the spinal cord become hyper-excitable. In these painful states, microglia receptors pick up a variety of signals from damaged neurons. In turn, the microglia secrete their own signals, causing neuroplastic increase in excitability and inflammation in pain fibers. Certain immune signals from microglia activate other signals that are toxic to nerve cells, even causing cell death.
There is an increase in microglia in the primary facial nerve during inflammation from dental procedures, and they also tend to increase in the hypothalamus after heart attack, causing pain. Microglia also are part of complex signaling related to morphine tolerance.
There is much more to learn about the conversations of microglia. Research is just now able to identify a single cell moving in a small brain territory. In the future, identifying microglia signals could help develop future treatments for a variety of brain diseases, including pain syndromes.