Reduced Neuronal Size and Glial Cell Density in Area 9 of the Dorsolateral Prefrontal Cortex in Subjects with Major Depressive Disorder

Abstract

Reductions in glial cell density and neuronal size have been described recently in major depressive disorder (MDD). Considering the important trophic influence of glia on neurons, we hypothesized that this glial cell deficit is more prominent close to neurons. In this investigation we have characterized neuronal and glia cytoarchitecture in prefrontal area 9 using spatial point pattern techniques and two-dimensional measures of cell size and density. In post-mortem brain tissue of subjects with MDD, schizophrenia, bipolar disorder (BPD), and normal controls (15 subjects per group), we examined the laminar location and size of all neurons and glial nuclei in a 500 microm wide strip of cortex extending from the pia to the grey-white matter border. In MDD, we observed reductions in glial cell density (30%; P = 0.007) in layer 5 and neuronal size (20%; P = 0.003) in layer 6. We also found that glial cell density (34%; P = 0.003) was reduced in layer 5 in schizophrenia, while neuronal size was reduced in layers 5 (14%) (P = 0.006) and 6 (18%; P = 0.007) in BPD. The spatial pattern investigation of neurons and glia demonstrated no alteration in the clustering of glia about neurons between control and patient groups. These findings confirm that glial cell loss and neuronal size reductions occur in the deeper cortical layers in MDD, but provide no support for the hypothesis that an altered spatial distribution of glia about neurons plays a role in the development of these changes.

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

“…The present observations of reductions in specific subpopulations of neurons immunoreactive for calcium binding proteins in MDD are in good agreement with earlier reports of reductions in the neuronal density and/or size of the Nissl-stained general population of neurons in the dlPFC and ORB regions in MDD (Cotter et al, 2002b(Cotter et al, , 2005Rajkowska et al, 1999). In those studies, neuronal pathology was observed in the same cortical layers (II-VI) as in the present study.…”

“…Morphometric studies in post-mortem tissue have demonstrated reductions in the average density and size of Nissl-stained neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD) (Cotter et al, 2002b(Cotter et al, , 2005Rajkowska et al, 1999). The neuronal pathology was most prominent in layer II of ORB and in layers II, III, V, and VI of dlPFC.…”

“…It was hypothesized that the density and size of CB-IR and PV-IR neurons would be altered in depression in prefrontal cortex (dlPFC and ORB), as reductions in the neuronal density and size of the Nissl-stained general population of neurons have previously been reported in these regions in MDD (Cotter et al, 2002b;Rajkowska et al, 1999Rajkowska et al, , 2005. It was also hypothesized that alterations in features of CB-IR and PV-IR neurons would differ between the two prefrontal regions, in light of the distinct laminar distribution for each of the two types of neuron.…”

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

“…As stress is associated with the risk of developing depression (Kessler, 1997;Kendler et al, 1999), the morphological findings of preclinical studies, where animals are exposed to chronic stressful experiences, are commonly related to the structural changes reported in the brains of depressed patients. In vivo imaging studies reveal selective volume reduction in the PFC (Drevets, 2000), and post mortem histological data show reductions in neuronal size and glial cell numbers in specific subregions of the frontal cortex in depressed patients (Ö ngür et al, 1998;Rajkowska et al, 1999;Cotter et al, 2001aCotter et al, , 2002Uranova et al, 2004). It is tempting to speculate that our finding on the pronounced changes in gliogenesis after chronic stress exposure may relate to the abnormalities of glial cell numbers reported in the frontolimbic areas of depressed patients.…”

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

“…Post-mortem studies of glial cell pathology in depression have reinforced this concept, although findings remain conflicted in many cases. [43][44][45][46] The observation of a significant misexpression of molecules central to both GABAergic and glutamatergic neurotransmission in the cortical areas of individuals with major depression has been previously documented by several groups. 21,23,47 These studies follow on a body of clinical evidence showing that antidepressant medications may reduce glutamatergic activity while raising cortical GABA levels, which are seen to be reduced in major depression 48,49 and possibly also schizophrenia.…”