Layer III pyramidal cells in the prefrontal cortex reveal morphological changes in subjects with depression, schizophrenia, and suicide

Abstract

Brodmann Area 46 (BA46) has long been regarded as a hotspot of disease pathology in individuals with schizophrenia (SCH) and major depressive disorder (MDD). Pyramidal neurons in layer III of the Brodmann Area 46 (BA46) project to other cortical regions and play a fundamental role in corticocortical and thalamocortical circuits. The AutoCUTS-LM pipeline was used to study the 3-dimensional structural morphology and spatial organization of pyramidal cells. Using quantitative light microscopy, we used stereology to calculate the entire volume of layer III in BA46 and the total number and density of pyramidal cells. Volume tensors estimated by the planar rotator quantified the volume, shape, and nucleus displacement of pyramidal cells. All of these assessments were carried out in four groups of subjects: controls (C, n = 10), SCH (n = 10), MDD (n = 8), and suicide subjects with a history of depression (SU, n = 11). SCH subjects had a significantly lower somal volume, total number, and density of pyramidal neurons when compared to C and tended to show a volume reduction in layer III of BA46. When comparing MDD subjects with C, the measured parameters were inclined to follow SCH, although there was only a significant reduction in pyramidal total cell number. While no morphometric differences were observed between SU and MDD, SU had a significantly higher total number of pyramidal cells and nucleus displacement than SCH. Finally, no differences in the spatial organization of pyramidal cells were found among groups. These results suggest that despite significant morphological alterations in layer III of BA46, which may impair prefrontal connections in people with SCH and MDD, the spatial organization of pyramidal cells remains the same across the four groups and suggests no defects in neuronal migration. The increased understanding of pyramidal cell biology may provide the cellular basis for symptoms and neuroimaging observations in SCH and MDD patients.

Scaling of smaller pyramidal neuron size and lower energy production in schizophrenia

“…Our finding of a smaller (−8.7%) mean size of DLPFC L3PNs in schizophrenia replicates prior reports using Nissl staining (−9.2%) ( Pierri et al, 2001 ) or Golgi labeling (−9.1%) ( Glantz and Lewis, 2000 ) in other cohorts of schizophrenia subjects, and are consistent with other studies reporting smaller sizes of L3PNs in in the illness ( Pierri et al, 2001 ; Rajkowska et al, 1998 ; Glantz and Lewis, 2000 ; Sweet et al, 2003 ; Sweet et al, 2004 ; Larsen et al, 2022 ). Previous findings suggest that smaller L3PNs in schizophrenia have fewer dendritic spines ( Glantz and Lewis, 2000 ; Garey et al, 1998 ; Konopaske et al, 2014 ).…”

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

“…Previous postmortem studies have also observed that changes in the morphological features of subiculum neurons were also similar yet more pronounced in schizophrenia patients compared to patients with mood disorders [69]. Another study, measured the Layer III pyramidal cells in the prefrontal cortex using postmortem tissue similarly revealed changes in the morphology of patients with major depression, and the changes were more exacerbated in neurons from schizophrenia patients [70]. This strengthens our results that neurons derived from patients with mood disorders (the co-twins) exhibit morphological and synaptic alterations that are stronger in patients with schizophrenia (the affected twins).…”

Analysis of networks in the dorsolateral prefrontal cortex in chronic schizophrenia: Relevance of altered immune response

“…In the context of SZ, decreased number of neurons has been identified in the layer three of DLPFC (van Berlekom et al, 2020). Besides, a study in the BA46 in DLPFC found morphological alterations in the pyramidal cells, however, the authors did not find an alteration in the spatial organization of pyramidal cells, suggesting a normal neuronal migration in SZ subjects (Larsen et al, 2022)In agreement with our study, CYFIP2 has also been found downregulated in a proteomic study in the cingulate anterior (Föcking et al, 2015). However, the relation between CYFIP2 negative symptoms has not been studied in SZ.…”