Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression

Abstract

Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 mm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p ¼ 0.013). Younger age of MDD onset correlated with fewer GNs (p ¼ 0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p ¼ 0.028) and controls (p ¼ 0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p ¼ 0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (po0.001), MDD*TCAs (po0.001), and controls (po0.001). Anterior GCL volume and GN number (r ¼ 0.594, p ¼ 0.001), and mid DG volume and GN number (r ¼ 0.398, p ¼ 0.044) were correlated. Anterior DG capillary density correlated with GN number (p ¼ 0.027), and with GCL (p ¼ 0.024) and DG (r ¼ 0.400, p ¼ 0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.

Dentate gyrus volume and memory performance in major depressive disorder

“…Furthermore, a recent in-vivo MRI study we performed (Huang et al, 2013) and post-mortem studies (Boldrini et al, 2013), reported increased DG volume and increased DG granule cell and glial cell numbers (Cobb et al, 2013) in MDD patients treated with antidepressants. These findings are consistent with the suggestion that stimulating DG neurogenesis with antidepressants might play an important role in reversing HC volume reduction in MDD patients.…”

“…In addition, preclinical studies have shown that stress-and glucocorticoid-induced suppression of DG neurogenesis can be prevented or reversed by antidepressant treatments, which also have direct neurogenic effects (Czéh et al, 2001;Pittenger and Duman, 2008;). In turn, recent post-mortem studies (Boldrini et al, 2013) and high field MRI studies (Huang et al, 2013) reported increased volume of the DG in MDD patients on antidepressant medications when compared to unmedicated MDD patients.…”

Association of Depressive Symptoms with Hippocampal Volume in 1936 Adults

“…They reported that participants with current depression, defined as a Center for Epidemiologic Studies-Depression Scale score X4 or current antidepressant use, had smaller hippocampal volumes. Studies in both living depressed patients (Sheline et al, 2003) and postmortem analyses (Boldrini et al, 2013) suggest that antidepressants may modify the association between hippocampal volume and depression. However, in the current report none of the analyses suggested a relationship between hippocampal volume and antidepressant, or other psychotropic medication use.…”

Adult Neurogenesis in Humans

“…To assess whether a decrease in hippocampal DG volume in antidepressant treated and untreated individuals suffering from MDD is a result of decreased neurogenesis, mature granule neuron number and DG and granule cell layer volume were determined (Boldrini et al 2013). Boldrini et al found that untreated MDD patients had fewer mature granule neurons in the anterior hippocampal DG than antidepressant treated or control individuals (a result consistent with imaging studies of McKinnon et al [2009]), as well as smaller DG and granule cell layer volumes (estimated stereologically using the Cavalieri method).…”