The role of the hippocampus in the pathophysiology of major depression

Abstract

Converging lines of research suggest that the hippocampal complex (HC) may have a role in the pathophysiology of major depressive disorder (MDD). Although postmortem studies show little cellular death in the HC of depressed patients, animal studies suggest that elevated glucocorticoid levels associated with MDD may negatively affect neurogenesis, cause excitotoxic damage or be associated with reduced levels of key neurotrophins in the HC. Antidepressant medications may counter these effects, having been shown to increase HC neurogenesis and levels of brain-derived neurotrophic factor in animal studies. Neuropsychological studies have identified deficits in hippocampus-dependent recollection memory that may not abate with euthymia, and such memory impairment has been the most reliably documented cognitive abnormality in patients with MDD. Finally, data from imaging studies suggest both structural changes in the volume of the HC and functional alterations in frontotemporal and limbic circuits that may be critical for mood regulation. The extent to which such functional and structural changes determine clinical outcome in MDD remains unknown; a related, but also currently unanswered, question is whether the changes in HC function and structure observed in MDD are preventable or modifiable with effective treatment for the depressive illness.

Fig. 1: Intrahippocampal pathways. The green line represents the direct intrahippocampal pathway from layer 3 of the entorhinal cortex (EC) to the CA1 region and then to the subiculum (SUB). From the subiculum, information can return to the entorhinal cortex or can enter the alveus (alv) and then the fimbria to influence neurotransmission in other cortical regions (red line). The afferent polysynaptic pathway is represented by the blue line. Axons from the entorhinal cortex enter the dentate gyrus (DG), and dendrites from the granule cells contact these glutamatergic axons. The mossy fibres of the granule cells project to the pyramidal neurons of the CA3 region, which then gives rise to efferent fibres to the alveus (in red) or Schaffer collateral fibres to the CA1 region. The pyramidal cells of the CA1 region, the primary output region of the cornu Ammonis, can project to either the subiculum (blue) or the alveus (red). Other regions displayed here include the perirhinal cortex (PRC), the parasubiculum (PaS) and the fusiform gyrus (FuG).

Fig. 2: Magnetic resonance spectroscopic images of the left hippocampus in a healthy control subject and in a patient with recurrent depression. The size of the difference shown here is unusually large, with most positive studies reporting a reduction in hippocampal complex (HC) volume of about 15% between cases and controls. Insert shows in blue the approximate sagittal level of the HC. Images were acquired on a 1.5-T GE Sigma Genesis–based EchoSpeed imager using previously published parameters. A: Sagittal view of the left HC, highlighted in red, of a healthy control subject whose left HC volume measured 3295 mm³. B: The patient whose left HC is represented here, with an HC volume of 2015 mm³, was of the same age and sex as the control subject but had a long history of recurrent depression.