How can the connections of the neuron (connectome) explain the mind, without including the cells that control all phases of synapse development and function? Astrocytes, the star shaped glial cells, are the most numerous cells in the brain. Glial cells outnumber neurons five to one (different ratios in different regions). Each astrocyte maintains its own region forming a weblike structure not overlapping others. Astrocytes are critical for thinking. In fact, astrocytes control synapse function in every phase.

Each astrocyte controls and communicates widely with many neurons. Astrocytes form a second strong barrier from intruders into the brain after they cross the blood-brain-barrier. Astrocytes maintain the ionic state of the extracellular matrix in the brain, and many other functions. They send their own signal waves, consisting of calcium spikes, over very long distances in the brain. They send nutrients to neurons, and digest old neuronal parts. They modify the neuronal signals. They secrete neurotransmitters, gliotransmitters, including glutamate. 

Astrocytes Determine fMRI Results

Importantly, astrocytes modulate and control blood flow in the brain with many feet circling the lining of the vessels. These end feet signal blood vessels to expand and contract, regulating blood flow. In fact, the fMRI actually measures the astrocyte activity, which controls the blood flow. The assumption used in the interpretation of fMRIs (not always correctly) is that this measured blood flow reflects the action of neurons. 

Through evolution the number of astrocytes have increased such that humans have the most and the biggest. An unusual finding is that in Einstein’s cortex, his astrocytes were noted to be unusually large and more complex than others. In humans, unlike other primates, the astrocytes have tentacles that travel through multiple layers of the cortex 6-layered structure.

Until recently, glial cells have been considered to be filler, or of secondary importance in brain function. A previous post showed the great importance of microglia in immune-brain interactions, and in pruning of synapses. Astrocytes have been considered as support cells in various ways, but only in the past years has their critical relationship to the synapses been uncovered.

Astrocytes are critical to all mental activity, controlling every phase of synaptic function.  

Astrocytes Control All Phases of Synapse Function

Recently, dramatic findings show that astrocytes are critical for the entire life cycle of synapses – their formation, neuroplasticity, normal function, and their pruning.

The two ways astrocytes control synapses are through secreted signals and direct contact.

A wide variety of critical factors have been found that are secreted by astrocytes, which are essential for information processing of the neurons.

There are three stages now identified of synapse development, all strongly influenced by astrocytes.

1. Early Synapse Formation: During the early stage of synapse development where axon and their leading edge boutons meet the dendrite’s leading edge spines. In this first phase elaborate structures are developed both inside the dendrites and axons and in the extra cellular space between. When the first structures of the synapses have been established in the glutamate excitatory neurons (which are the majority of all neurons), two types of receptors are necessary for function. The first of the two is the NMDA receptor, which is established in this phase in what is known as a silent synapse because it cannot function without the second receptor type.

1. Synapse Maturation: The second phase is known as maturation where the structure that has been established and is able to begin to send signals with neurotransmitters, respond to the neurotransmitters with appropriate receptors triggers an action potential along the post synaptic axon. In the glutamate type synapse, the second necessary type of receptor, AMPA, is added in this phase to make the synapse functional.

1. Synapse Neuroplasticity and Pruning: The third phase is when a synapse changes through neuroplasticity or is eventually no longer useful and is eliminated. These processes occur in conjunction with many new synapses that enlarge and alter the signaling. Neuroplasticity effects add new synapses and prune those that are being usurped with the new functions.

Neurons Alone Are Not Enough for Synapse Function

Neuroscience has focused on neuronal activity related to the synapses. But, despite the large amount known about the neuron, it is very inadequate to describe the three phases of the synapse function.

In fact, neurons rely on astrocytes to help control synaptic function. The bidirectional communication between the astrocyte and the neuron is very elaborate.

In the fetus the neural precursor stem cells first generate neurons, at the fantastic rate of 250,000 per second during the last month of pregnancy, establishing one trillion neurons before 900 billion are pruned by programmed cell death pathways. The astrocytes are the second brain cell that is developed from the neuronal precursor stem cells. The astrocytes are largely completed soon after birth but continue to be produced during the first period when synapses are formed in the infant. The stem cells that create new neurons in the hippocampus have characteristics of astrocytes. In general, astrocytes form much of the structure of the extracellular brain space. When new neurons in adult brains migrate the long distance from where they are born to their final destination they find a path made of tunnels created by astrocytes. Recently, it has been shown that infant neurons secrete Slit1, which is received by astrocytes as a signal to create the tunnel for travel.

In fact, astrocytes secrete a factor that inhibits stem cell creation of new neurons and then when this factor is decreased new cells are created.

While a single neuron can have as many as 100,000 synapses, with an average of 10,000 per neuron, the astrocytes also have a great reach, each contacting 100,000 neurons. Astrocytes, like neurons, produce neurotransmitters, have receptors in their membranes and have ionic channels, and have their own calcium based action potential that sends signals around the brain. This allows the astrocytes to stay in constant communication with neurons.

The Formation of Synapses: First Phase of Synapses

Much of the research into astrocyte synapse function has been in the major excitatory glutamate system, which has been estimated to be 60 to 70% of the neurons in the brain.

First, it was noted that without glial cells, retinal ganglion neurons did not form synapses. Then it was found that if cultured with astrocytes they produced a greater amount of synapses. It was noted also that if just the fluid that had housed astrocytes was used to culture neurons, they grew ten times as many synapses. Later, this same result was found in other regions such as the hippocampus, the cortex, spinal motor neurons, and cerebellar neurons.

Astrocytes secrete many extremely vital factors. Without these factors synapses will not form or function.

Apolipoprotein E: The first signal discovered that could stimulate synapses was astrocyte produced apolipoprotein E which is bound to cholesterol. This particular signal is instrumental in the creation of the vesicles that carry the neurotransmitters to be released at the synapse. It also has many other functions, some related to Alzheimer’s disorder.

Thrombospondins: Very recently, it was discovered that the astrocyte secreted thrombospondins (TSP or THBS). These large proteins in the extracellular matrix are critical for forming excitatory synapses. During fetal development there is a great amount of TSP, and without it no functional synapses. There are different TSP proteins, some active in the fetus and some later in the adult brain. In fact, adult humans have a greater amount of TSP than animals, which might correlate to the greater neuroplasticity in human brains.

TSP appears to have a primary role in stimulation of synapses.

TSP functions by stimulating the α2δ-1 calcium channels in the neuron. Through a very complex action, stimulation of the calcium channels draws more critical proteins that build the adhesion and scaffolding necessary for the synapse. Two of these critical factors have been mentioned in several previous posts, postsynaptic neuroligins and presynaptic integrins. TSP is critical in many of signaling pathways in the extracellular matrix including protein kinase A.

Hevin: Yet another critical astrocyte secreted factor is called hevin, which is part of a large important family of SPARC proteins. Hevin is critical in adult brain synapse formation. Some of the other SPARC proteins have opposing effects to hevin.

Hevin is critical to increasing the size of the synapse with important interactions with neureglin and with integrin, both of which bind to hevin.

Hevin appears to have primary role in maintenance of the synapse. 

With SPARC antagonistic to hevin, it appears that this antagonism makes synapses return to an earlier state allowing neuroplasticity, or pruning of synapses.

TSP and Hevin bring synapses to the silent state, before they become full excitatory neurons with both NMDA and AMPA receptors in the membrane.

Astrocytes are Critical for Both Inhibitory and Excitatory Neurons

The brain consists of, perhaps, 60 % excitatory neurons and 40% inhibitory neurons. Although the early research was done with glutamate it is now known that astrocytes are critical for both.

GABA or inhibitory networks form first in the fetus, but function as excitatory until later when they become inhibitory in babies and adults. Astrocytes promote both excitatory and inhibitory neurons. They secrete factors to help both the pre and post synaptic neurons. Astrocytes factors in medium increased GABA A current, length and branching of GABA. These factors are not yet known. 

Astrocytes Contact Neurons

In the hippocampus 60% of synapses are contacted by astrocytes. A movie has been made of astrocyte touching the synapses, which increases synapse activity, both strength of current, and the number of synapses. By touching the neuron, a protein kinase C signaling cascade is used involving integrin.

When neurons are first created they cannot receive a synapse but must learn how to do this. Contact by astrocytes allowed neurons to receive synapses. This process whereby astrocytes allow neurons to receive synaptic connections uses neurexin, which is an adhesion molecule that is on the surface of dendrites. This process has been found for hippocampus, but processes in other regions, using specific factors, are just being researched.

Synapse Maturation Process: Second Phase

A magnesium molecule blocks NMDA receptor channels. In order to allow current to flow, AMPA activation allows the magnesium to move and allow the flow of ions into the channel, allowing function of the neuron.

Astrocytes produce vital factors for the maturational process.

Glypicans: Glypicans are lipid-protein molecules that sit on the outside of the membrane.  A process releases the protein that stimulates the production of AMPA receptors in the glutamate membrane that along with NMDA receptors allows full functioning of excitatory neurons.

Glypican also stabilizes dendritic spines, which change very rapidly and often. They are constantly being built and broken down by assemblies of tubules.

Ephrins: Other astrocyte factors are ephrins, which in contact with a neuronal receptor, allows synapses to grow and mature. Ephrin is also critical in controlling stem cells that make new neurons. Ephrin-A2 and A3 keep the stem cells in a dormant state, and when it is inhibited then new neurons are minted.

Astrocytes Modulate Neurons by Touching Them

When neuroplasticity is down regulated the spines shrink and the AMPA disappear. When the synapses are strengthened by neuroplasticity the AMPA increases and the spines become much more stable. The shape of the spines dramatically and rapidly changes based on activity of the neuron.

The astrocytes are observed having processes that wrap around the dendritic spines (not presynaptic terminals). The astrocytes arms are noted to rapidly move and change, like an amoeba. They move their processes in and out until they can accurately contact the spines. The larger and longer lasting spines of strong neuroplastic connections have much more permanent connections of the astrocyte arms.

The speed of the astrocyte processes is much slower than the action potential of the neuron and many action potentials are necessary to change the calcium signaling in the astrocyte.

Another function of the astrocyte processes is taking up the glutamate once it is released into the synaptic space between the pre and postsynaptic neurons. When glutamate floats out of the immediate space it stimulates many more dendrite spine heads to be built. The astrocyte in this moment removes its arms to allow the new spines to form then wraps around the spines that are to be functional.

Synapse Pruning: The Third Phase

The precision of the brain is maintained by the pruning of synapses to allow new ones to take over functions, or to refine, strengthen, or decrease the exact signal.

The remodeling of neurons is constantly occurring with neuroplasticity, stimulated by changing sensory input and new learning. Pruning is a critical element of neuroplasticity.

It was shown in a previous post that microglia, another important glial cell, tied to immune function, are involved in pruning the synapse. (See my Guest Blog for Scientific American Mind, “Wired and Wireless Components of the Brain).

But, also astrocytes appear to control elimination. It turns out that it is the signals from the astrocytes than attract the immune mechanisms involving the complement system. The astrocytes stimulate the first signal of the complement cascade, C1q.

Complement tags debris to be removed by macrophages and other phagocytic cells including microglia. Microglia have multiple receptors for complement. Microglia are known to eat motor neuron damage.

The microglia are called by the astrocytes, surround the synapses, in both pre and post synaptic regions.

Remarkably, in some cases, astrocytes themselves phagocytize neuronal debris after trauma, or glioma cancers. Astrocytes use many genes that are related to phagocytosis.  In brain injury astrocytes are stimulated to eat entire dead cells, as well as some healthy cells, for example in neuron destruction in glaucoma.

Astrocytes and Brain Disease

Autism and schizophrenia appear to be diseases of synapses. In several important genetic brain diseases, Rett syndrome, fragile X syndrome and Down’s syndrome, abnormal astrocytes are a major part of the problem.

Rett disability includes autism and cognitive loss, as well as decrease in brain size. A genetic repressor has been found in this disease that originates in astrocytes (MECP2). When MECP2 is deficient in astrocytes the disease develops. In fact, this may be under control the production of TSP, hevin or glypicans. In Downs TSP is reduced.  Astrocytes therefore contribute to the synapse abnormalities in Downs. Epilepsy is another disease related to synapses and to astrocytes. Astrocytes are now known to be critical in psychiatric illness, such as schizophrenia and autism, which develop from imperfect synapses in all three phases.

Brain Evolution

Many scientists assume that increased neuronal connections are the cause of increased cognition in humans. But, it is possible that evolution of astrocytes allowed greater control over synapses as a major spur of brain evolution. The glial cells have evolved more rapidly than neurons compared with other animals. In general the larger the brain the more glial cells. Nematodes have few glia; fruitflies have 25% glia; and the mouse has 65% glia.

Compared with other primates humans have a much greater ratio of glia to brain cells, particularly astrocytes which vary in different brain regions: cerebellum the least, then cortex, and the most in the basal ganglia and brainstem. Recent study of genes in primates and humans found that thrombospondin gene was one of two that was much more utilized in human brains than other primates. Also, when human astrocytes were placed in mouse brains, many more synapses were produced. 

Astrocytes Control All Phases of Synapses

Astrocytes are vital to the function of the brain and to thinking. They are the second brain cell produced after neurons, and take up 50% of the brain’s volume, forming connections to neurons and blood vessels in their region. The astrocyte’s feet on the blood vessels dilate and contract stimulating blood flow, and the fMRI signal.

But, most vitally, astrocytes control all phases of synapses  – forming, maturation, neuroplasticity, and pruning.

How can we know how the brain works without understanding half of the cells, especially those that are providing and nurturing the synapses? Astrocytes have a completely different type of calcium signaling wave.

Astrocytes, along with many issues outlined in previous posts, present another enormous challenge in understanding the complexities of the brain. In fact, how can mapping neuronal connections of the brain (the connectome) determine how the mind works, without understanding what controls the connections? Any map of the brain must include the astrocytes.