Antidepressant medications allow millions who are afflicted with major depressive illnesses to resume normal, fulfilling lives, but despite knowing what the drugs do, neuroscientists are less certain about why they work. Drug treatments for major depression were stumbled upon by accident, not by a clear view of what has gone wrong in parts of the brain controlling mood, motivation, and arousal. Modern antidepressants were developed from the chance observation that a drug used to treat tuberculosis in the 1950s had mood-elevating side-effects. Part of the difficulty in understanding the cause of major depression may stem from faulty assumptions shared by most neuroscientists-the presumption that the problem was with neurons. New research suggests that this assumption may not be entirely correct.
Neurons communicate with other neurons through synapses, and this is where drugs for treating most mental illnesses operate. Synapses are points of close contact between two neurons where chemical signals (neurotransmitters) are released from the signaling neuron and received by the next neuron in the circuit. Most people are familiar with how synapses look and operate from textbooks and television advertisements for drugs to treat a wide range of psychiatric and neurological illnesses. The neurotransmitter chemical is packaged in tiny bubbles, called synaptic vesicles, which accumulate inside the stumpy ending of the neuron. When an electrical impulse reaches them, the bubbles burst open and release their contents into the synaptic cleft, which is the microscopic space separating the two neurons. The neurotransmitter stimulates the receiving neuron, and in this way a signal is transmitted through chains of neurons in a circuit. The neurotransmitter is then pumped out of the synaptic cleft rapidly to allow another message to be sent. But something vital is missing from this textbook description. Before revealing this omission it will be helpful to consider one of the most widely prescribed categories of antidepressants, the serotonin reuptake inhibitors (SSRIs).
These drugs inhibit the molecular "pumps" that remove the neurotransmitter serotonin from the synapse after it has been released by a neuron. Slowing neurotransmitter reuptake prolongs the chemical stimulation of the receiving neuron, allowing stronger signaling across the synapse. The effectiveness of SSRIs in treating major depression bolstered the theory that this and other mental illnesses are caused by an imbalance in neurotransmitters in the brain. SSRI's are thought to work by restoring the proper neurotransmitter balance.
Something Is Missing--the Overlooked Clue
The synapses familiar from textbooks and drug advertisements are missing a vital part of the synapse, a colossal oversight in neuroscience for the last 100 years that is only now beginning to be corrected. Tightly surrounding the synapse are brain cells that encase the synapse, but these cells are never shown in most illustrations. Called glia (meaning glue), these brain cells were ignored because they do not fire electrical impulses like neurons do, and thus glia were regarded as a cellular filler between neurons, binding them together into brain tissue. There seemed no need to draw the "glue" sticking neurons together, so glia are left out of the illustrations of synapses and dismissed from the minds of most doctors and neuroscientists.
Recently neuroscientists have come to appreciate that glia are far more than brain glue. Glia comprise 85% of all cells in the human brain, and they are vital to every aspect of brain health and function. One type of glial cell, called an astrocyte, is the brain's natural neurotransmitter re-uptaker. Astrocytes take up neurotransmitter released by neurons at synapses, because neurons, as a general rule, do not have the re-uptake mechanisms to clear neurotransmitter from the synapse. (Serotonin is something of an exception because both glia and neurons work together to remove this neurotransmitter from synapses.)
Considering their important role in neurotransmitter re-uptake for synaptic communication, glia are in a pivotal position to cause or cure major depression and other mental illnesses resulting from faulty neurotransmitter regulation. This new awareness of glia (which I call "the other brain" because it has been neglected by a century of neuroscientists fixated on neurons) opens a new avenue in the search for new drugs to treat major depression and other illnesses that result from sluggish or overactive synaptic transmission. At the same time, glia defective in neurotransmitter re-uptake could be a fundamental cause of mental illnesses.
Given what we now know about glia, it is certain that many of the drugs being used to treat these illnesses also act directly on glia, because glia have the same neurotransmitter receptors that neurons use to communicate at synapses. These receptors allow glia to eavesdrop on signaling between neurons at synapses. Moreover, neuroscientists have recently discovered that astrocytes can release the same neurotransmitters that neurons use to communicate. This allows glia to sense signaling between neurons and control neural circuits by regulating the re-uptake of neurotransmitters or by releasing neurotransmitters into synapses.
Prozac and Glia in the Birth of New Neurons
It is becoming clear that glia are also involved in treatments for major depression in other important and surprising ways. Glia release powerful growth-promoting substances, called neurotrophic factors, that stimulate the growth of neurons, protect neurons from injury and death under adverse conditions, and even stimulate the birth of new neurons in the adult brain. This is important because recent research has found that nearly all the antidepressant medications used to treat major depression stimulate the birth of new neurons in a part of the brain vital for memory, the hippocampus. Mature neurons cannot divide, so new neurons are not born from other neurons. Recent research has found that immature glial cells are the source of new neurons in the adult brain.
Could SSRI's stimulate the secretion of neurotrophic factors that would promote the birth of new neurons? A study by Ana Carolina Tramontina and colleagues published in the scientific journal Progress in Neuro-Psychopharmacology and Biological Psychiatry, found that the widely prescribed SSRI, Prozac (fluoxetine), causes astrocytes to release a protein called S100. This protein is a well-known neurotrophic factor that controls cell proliferation, growth, and survival. It has been known for a decade that the amount of S100 protein increases in the blood of patients with major depression when treated with SSRIs, and the level of S100 correlates with the therapeutic recovery, but the source of the protein and why it became elevated were unclear.
In a surprising twist, further experiments by the researchers revealed that this effect of Prozac was not produced by the well-known action of the drug in suppressing serotonin re-uptake to increase serotonin levels. Prozac must be stimulating glia in another way to release this neurotrophic protein, which could stimulate the birth of new neurons in patients treated with SSRIs.
The search for better treatments for major depression depends on a better understanding the biology gone wrong in this illness. The answer to this question remains elusive, but the growing appreciation of "the other brain" suggests that the search until now has been too narrow. New thinking is leading researchers in a new direction-on a search beyond neurons.
Further Reading
Fields, R. D. (2010) The Other Brain, Simon and Schuster, NY,. http://theotherbrainbook.com
Tramontina, A.C. et al., (2008) Secretion of S100B, an astrocyte-derived neurotrophic protein, is stimulated by fluoxetine via a mechanism independent of serotonin. Progress in Neuro-Psychopharmacology and Biological Psychiatry 32: 1580-83.
