In 2000, researchers from the Yale University School of Medicine made a surprising discovery that would start to change the way we think about the causes of depression. Ronald Duman and his colleagues chronically administered different classes of antidepressants to rats, and found that this stimulated the growth of new neurons in the hippocampus. As a result, researchers and clinicians began to think of depression as something like a mild neurodegenerative disorder, rather than as a chemical imbalance in the brain.
Earlier studies had already suggested that depression involves shrinkage of the hippocampus caused by death of cells in that part of the brain, and the findings of Duman’s group further suggested that antidepressants may be effective because they prevent or reverse the loss of cells. Despite a lack of direct evidence for this, the findings have opened up an avenue for the development of new treatments for depression: earlier this year, for example, a company in San Diego began a clinical trial to test the efficacy of a compound which stimulates neurogenesis.
Researchers from the University of Texas Southwestern Medical Center now provide direct evidence that antidepressants work by stimulating neurogenesis. They show that a receptor for a molecule called brain-derived neurotrophic factor (BDNF) governs neurogenesis induced by antidepressants, and is required for sensitivity to these drugs. As well as showing that the effectiveness of antidepressants is indeed dependent on their ability to stimulate neurogenesis, the findings may also begin to shed light on why a large proportion of depressed patients do not respond to medication.
BDNF and other growth factors play essential roles during embryogenesis, but their functions are not restricted to development, and BDNF in particular has previously been implicated in depression. BDNF levels in the rodent hippocampus are elevated in response to chronic exposure to antidepressants; infusion of BDNF into the hippocampus stimulates neurogenesis and produces antidepressant-like effects in behavioural tests; and mutant mice with reduced BDNF levels have blunted responses to antidepressants.
These observations strongly suggest that BDNF is involved in mediating the response to antidepressants of neural progenitor cells (NPCs) in the hippocampus. It is because of the presence of NPCs that new cells can be generated in the hippocampus throughout life. They have stem cell-like properties and retain the ability to divide asymmetrically, thus propagating themselves while at the same time generating new neurons which can be incorporated into existing hippocampal circuits.
With this in mind, Li et al generated several strains of mutant mice lacking the BDNF receptor TrkB. The mutants created conditional knockouts; in other words, they were engineered in such a way that they lacked the TrkB receptor only in specific cell types at specific times. (The researchers used the Cre-LoxP system to generate the mutants.) In one strain of mutants, expression of the receptor was disrupted in NPCs either during embryonic development or in adulthood; in another, TrkB expression was disrupted in differentiated cells throughout the hippocampus.
Those mutants in which TrkB expression was deleted during embryonic development were born with brains of a normal size. Beginning at postnatal day 10, they exhibited a 30% reduction in hippocampal volume, which persisted throughout adulthood. This is interesting, as it suggests that the mechanisms governing cell proliferation during embryonic and postnatal development are different from one another. In the second strain of mutants, in which the receptor was deleted in adulthood, there was a significant decrease in the number of newly-generated hippocampal neurons. In the third strain, deletion of the receptor from differentiated neurons had no apparent effect.
These findings show that the actions of BDNF on progenitor cells, mediated by TrkB, is necessary for the normal proliferation of cells in the hippocampus, both in newborn and adult mice. They were confirmed by a further experiment in which cells were isolated from the dentate gyrus of the embyronic and adult mutants lacking TrkB in the progenitor cells, and then grown on culture dishes. Under these conditions, the cells spontaneously aggregated to form spherical clusters called neurospheres, which increased in size when BDNF was added to the culture medium. Thus, the growth factor acts directly on NPCs to induce proliferation.
The mutants lacking the TrkB receptor in the NPCs were then treated with fluoxetine (Prozac), imipramine (a tricyclic antidepressant) or saline (salt water) for 3 weeks and the amount of time they took to begin feeding was recorded and compared to healthy control mice. This is a behavioural measure of depression-like symptoms – in animal models, “depressed” mice take longer than healthy ones to reach for food. In this test, the healthy mice that were treated with either antidepressant showed a much shorter latency to feeding compared with the controls given saline and the mutants.
The animals were subjected to the tail-suspension test, which is a measure of stress. When suspended by their tails, healthy animals and those treated with antidepressants quickly become immobile; this is a sign of despair in response to a stressful situation from which they cannot escape. This time, the control mice treated with either fluoxetine or imipramine quickly became immobile when suspended, whereas the mutants treated with the same drugs did not.
When the animals’ brains were examined, it was found that the mutants treated with both antidepressants and those who had exercised on the running wheel had significantly fewer newly-generated hippocampal cells than controls. Likewise, voluntary exercise on a running wheel induced hippocampal neurogenesis in control mice but not in the mutants. In all these tests and analyses, mice lacking the TrkB receptor in differentiated hippocampal neurons were comparable to the controls.
Together, these findings show that deleting the BDNF receptor TrkB from hippocampal progenitor cells, but not differentiated neurons, make embryonic and adult mice insensitive to the effects of two different classes of antidepressants. The study provides a direct link between BDNF, neurogenesis and the beneficial effects of antidepressants. It shows that two classes of antidepressants – SSRIs and tricyclics – exert their effects by stimulating neurogenesis, and that this effect is mediated by BDNF. The molecular mechanism by which this occurs is, however, still unknown, and is likely to be the focus of future work.
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Li, Y et al (2008). TrkB Regulates Hippocampal Neurogenesis and Governs Sensitivity to Antidepressive Treatment. Neuron 59: 399-412. DOI: 10.1016/j.neuron.2008.06.023