Molecular and cellular hypotheses of antidepressant actionThe possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death
Introduction
The introduction of the monoamine oxidase inhibitors, now many decades ago, ushered in the era of depression being viewed as a biochemical disorder. There has been unabated interest since then in the neurochemical underpinnings of the disease, as norepinephrine, dopamine, and serotonin have swung in and out of fashion.
More recently, there has been interest in the fact that major and prolonged depression appears to also involve morphological changes in the brain Bremner et al 2000, Sheline et al 1996, Sheline et al 1999. In this special issue of Biological Psychiatry there will be frequent attention paid to the decrease in depression in the volume of the hippocampus, a structure that plays a vital role in learning and memory, contextual fear conditioning, and neuroendocrine regulation. Such atrophy, of as much as approximately 20% of hippocampal volume, is demonstrable after controlling for total brain volume or volume of the amygdala or temporal lobe. Moreover, atrophy increases with longer durations of depression and persists up to decades after depressions have resolved Bremner 1999, Sheline et al 1996, Sheline et al 1999.
This is a striking finding, prompting obvious interest as to the possible cellular mechanisms underlying it. One possibility to be considered in some articles is that depression induces regression of dendritic processes. Another is that there is inhibition of neurogenesis (a phenomenon whose demonstration in the adult hippocampus, including in humans, is revolutionary [Eriksson et al 1998, Gould et al 1999]). A final possibility is that prolonged depression causes overt loss of hippocampal neurons.
A second idea that will be aired in subsequent articles is that glucocorticoids, the adrenal steroids secreted during stress, contribute to the hippocampal atrophy. The subtypes of depression most associated with hippocampal atrophy involve hypersecretion of glucocorticoids Sheline et al 1999, Whiteford et al 1987. Moreover, these hormones have various adverse effects that are either most pronounced or are limited to the hippocampus, including 1) inducing regression of dendritic processes; 2) inhibiting neurogenesis; 3) impairing the ability of neurons to survive coincident insults, thereby worsening the neurotoxicity of seizure, hypoxia–ischemia, metabolic poisons, hypoglycemia, and oxygen radical generators; 4) with sufficient exposure to excessive glucocorticoids, neurotoxicity. The last effect is limited to the CA3 cell field in the hippocampus, and in evaluating the mechanisms underlying such neurotoxicity, to be discussed below, it is important to note that this area has no higher concentrations of corticosteroid receptors than some brain regions (reviewed in Gould et al 1999, Reagan and McEwen 1997, Sapolsky 1999). Moreover, selective atrophy of the hippocampus occurs in Cushing syndrome, in which there is hypersecretion of glucocorticoids, and in posttraumatic stress disorder, in which there are either elevated levels of glucocorticoids (e.g., Pitman and Orr 1990) or enhanced target tissue sensitivity to glucocorticoids (e.g., Yehuda et al 1991; reviewed in Bremner 1999, Sapolsky 1996, Sapolsky in press).
This review is prompted by the possibility that hippocampal atrophy in depression does involve glutamatergic neuron loss, and that glucocorticoid excess plays a role in this loss. Its purpose is twofold: to review current thinking about the mechanisms by which hippocampal neurons die during insults and the facets of such neuron death that are sensitive to glucocorticoids.
Section snippets
Hippocampal neuron death: a broad outline
The hippocampus is either the most or among the most vulnerable of brain regions to neuron loss arising from seizure, hypoxia–ischemia, and hypoglycemia. This vulnerability has inspired considerable research as to its underlying causes.
From this has emerged something resembling a central dogma (Lee et al 1999) centered around the preponderance of synapses in the hippocampus making use of glutamate as a neurotransmitter. This is the most excitatory neurotransmitter known, and this property,
Recent insights regarding glutamatergic neurotoxicity
I will now describe some of the most interesting and important modifications in this picture that have emerged more recently. Predictably, the bulk of them demonstrate that the “truths” presented above are a bit less certain than originally thought.
Glucocorticoids and their adverse effects in the hippocampus
The hippocampus is one of the principle glucocorticoid target sites in the brain, with ample concentrations of corticosteroid receptors. When glucocorticoid levels rise into the mild stress range for a few hours, they can enhance cognition by facilitating aspects of synaptic plasticity in the hippocampus (for a review, see McEwen and Sapolsky 1995). This has been speculated to make some teleologic sense—memory is not automatically consolidated concerning all events occurring in the environment
Conclusions
This review has had two goals. The first has been to orient the reader toward current thinking about how hippocampal neurons die in response to insults. As was seen, a number of themes dominate these pathways of neurodegeneration. These include the idea that normative cellular physiology that mediates a critical aspect of cognition (learning and memory) can, when writ large, become pathophysiology. Another is that with a neurotransmitter as excitatory as glutamate, and with an ion as
Acknowledgements
Aspects of this work were presented at the conference “Depression in the Twenty-First Century: New Insights into Drug Development and Neurobiology,” February 21–22, 2000, Dana Point, California. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided jointly by Pharmacia & Upjohn and Janssen Pharmaceutica.
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