Cell atrophy and loss in depression: reversal by antidepressant treatment

Abstract

Depression is associated with structural alterations in limbic brain regions that control emotion and mood. Studies of chronic stress in animal models and postmortem tissue from depressed subjects demonstrate that these structural alterations result from atrophy and loss of neurons and glial cells. These findings indicate that depression and stress-related mood disorders can be considered mild neurodegenerative disorders. Importantly, there is evidence that these structural alterations can be blocked or even reversed by elimination of stress and by antidepressant treatments. A major focus of current investigations is to characterize the molecular signaling pathways and factors that underlie these effects of stress, depression, and antidepressant treatment. Recent advances in this research area are discussed and potential novel targets for antidepressant development are highlighted.

Figure 1. Schematic of a synapse and cellular alterations caused by stress and depression

Shown in the diagram on the top are the major synaptic elements, including pre- and postsynaptic sites, a glial cell (astrocyte), and inhibitory GABAergic input. Glutamate neurotransmission is controlled by signaling pathways that regulate neurotransmitter release at the presynaptic level and ionotropic glutamate receptors and neuroplasticity response pathways at the postsynaptic site. Astrocytes control the reuptake and inactivation of glutamate, as well as cycling of glutamate precursor, glutamine back to the presynaptic element. GABAergic input provides critical tonic inhibition of excitatory neurons. The diagram on the bottom shows the alterations of the cellular components, as well as signaling pathways, caused by stress and depression in each of these synaptic elements. Arrows indicate the direction of effect up or down. See text for further details.