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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 μm), 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=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). Anterior GCL volume and GN number (r=0.594, p=0.001), and mid DG volume and GN number (r=0.398, p=0.044) were correlated. Anterior DG capillary density correlated with GN number (p=0.027), and with GCL (p=0.024) and DG (r=0.400, p=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.

SUBMITTER: Boldrini M

PROVIDER: S-EPMC3629406 | biostudies-other | 2013 May

REPOSITORIES: biostudies-other

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Project description:Baicalin isolated from Scutellaria baicalensis possesses antidepressant abilities through its relation to hippocampal neurogenesis. Current research has found that baicalin can promote the proliferation of hippocampal granule cells, however, the detailed mechanism of baicalin on the survival and maturation of hippocampal granule cells has yet to be sufficiently explored. The purpose of this study was to evaluate whether baicalin could facilitate the survival and maturation of hippocampal granule cells, and to explore its potential mechanism. The chronic corticosterone (CORT)-induced mouse model of depression was used to assess antidepressant-like effects of baicalin and to illuminate possible molecular mechanisms by which baicalin affects hippocampal neurogenesis. The survival and maturation of granule cells were measured by immunohistochemistry, immunofluorescence and Golgi staining. The expression of Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β)/β-catenin pathway related proteins were measured by western blot analysis. PI3K inhibitor LY292002 and AKT inhibitor Perifosine were administered to HT-22 cells to explore the relationship between the PI3K/AKT/GSK3β/β-catenin pathway and baicalin. The results of the study illustrated that baicalin significantly decreased chronic CORT-induced depressive-like behaviors and reduced serum corticosterone levels. In addition, baicalin (administered at 60 mg/kg) reversed chronic CORT-induced lesions on hippocampal granule cells. Moreover, baicalin significantly increased the phosphorylation rate of PI3K, AKT, GSK3β, and total β-catenin. The study found that administration of LY292002/Perifosine counteracted the effects of baicalin in HT-22 cells. These results demonstrate that baicalin can alleviate chronic CORT-induced depressive-like behaviors through promoting survival and maturation of adult-born hippocampal granule cells and exhibiting protective effect on hippocampal neuron morphology. We propose the underlying mechanisms involve the activation of the PI3K/AKT/GSK3β/β-catenin pathway.

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Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression.

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