FEATURE ARTICLE
Depression and the Birth and Death of Brain Cells
The turnover of neurons in the hippocampus might help to explain the onset of and recovery from clinical depression
Henriette van Praag, Barry Jacobs, Fred Gage
Stimulation from Serotonin
As mentioned above, prescription drugs that increase serotonergic neurotransmission are currently the most common and most effective treatment for depression. Furthermore, serotonin stimulates cell division in a variety of peripheral tissues and triggers neurogenesis in the central nervous system during development. It also plays an important role in neuronal and synaptic plasticity. That evidence made serotonin worthy of further study.
Recently, one of us (Jacobs) and his colleagues used adult rats to study the effect of d,l-fenfluramine, a drug that releases serotonin throughout the central nervous system. In those studies, systemic administration of that drug increased cell division two- to threefold in the dentate gyrus. Moreover, an antagonist for a specific serotonin receptor—called 5-HT1A (serotonin is also known by the name 5-hydroxytryptamine, or 5-HT for short)—completely blocked this effect of d,l-fenfluramine. (Other serotonin receptors might also be involved in this process.) We later showed that much of this increase in cell division ended up making more neurons. So these studies highlight serotonin's impact on granule-cell neurogenesis in an adult rat's dentate gyrus.
The clinical benefit of drugs that increase serotonergic neurotransmission encouraged one of the authors (Jacobs) to test fluoxetine (Prozac), which increases brain levels of circulating serotonin by inhibiting it from being taken back into neurons that release it. We gave adult rats a three-week, systemic treatment of fluoxetine and found an approximately 70-percent increase in the number of cells produced in the dentate gyrus. Ronald Duman's group at Yale University confirmed and extended that result. They found that fluoxetine, antidepressants acting preferentially on norepinephrine and chronic electroconvulsive shock all increased cell proliferation in a rat's dentate gyrus.
In combination, the above studies demonstrate that serotonin can dramatically augment cell proliferation and that it does so, at least in part, by action at the 5-HT1A receptor. Consistent with this, the hippocampus—especially the dentate gyrus—has an extremely dense concentration of these receptors.
If this receptor plays a role in depression, it would be useful to test 5-HT1A-agonist drugs as therapeutic agents. Unfortunately, we lack a potent and specific 5-HT1A-receptor agonist for human use. Partial agonists for the 5-HT1A receptor, however, can reduce anxiety and provide some antidepressant effect. To better understand this possible mechanism, we must examine 5-HT1A function in depressed patients. Sharon Cheetham and her colleagues at University College, London did report a decreased number of 5-HT1A binding sites in the hippocampus of depressed suicide victims, but they did not examine specific 5-HT1A binding in the hippocampus. More recently, Stanley Watson and his colleagues at the University of Michigan reported a decrease in the expression of 5-HT1A mRNA in the hippocampus in a group of depressed suicide victims. These findings provide additional support for this receptor's importance in controlling depression.
A final feature of this hypothesis is that it provides a conceptually simple explanation for the therapeutic lag, in which antidepressant treatments—both drugs and electroconvulsive therapy—typically require 3–6 weeks to become effective. We suggest that this is because it takes time for newly born dentate-gyrus neurons to fully mature, extend their neurites and integrate with the existing brain circuitry.
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