Increased doublecortin (DCX) expression and incidence of DCX-immunoreactive multipolar cells in the subventricular zone-olfactory bulb system of suicides.

Marissa E Maheu,Naguib Mechawar,Maria Antonietta Davoli,Julia Devorak,Alexander Freibauer,Gustavo Turecki

doi:10.3389/fnana.2015.00074

Marissa E Maheu, Naguib Mechawar + Show 4 more

Open Access

https://doi.org/10.3389/fnana.2015.00074

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Abstract

Postmortem studies have confirmed the occurrence of adult hippocampal neurogenesis in humans and implicated this process in antidepressant response, yet neurogenesis in other regions remains to be examined in the context of depression. Here we assess the extent of subventricular zone-olfactory bulb (SVZ-OB) neurogenesis in adult humans having died by suicide. Protein expression of proliferative and neurogenic markers Sox2, proliferating cell nuclear antigen, and doublecortin (DCX) were examined in postmortem SVZ and OB samples from depressed suicides and matched sudden-death controls. In the SVZ, DCX-immunoreactive (IR) cells displayed phenotypes typical of progenitors, whereas in the olfactory tract (OT), they were multipolar with variable size and morphologies suggestive of differentiating cells. DCX expression was significantly increased in the OB of suicides, whereas SVZ DCX expression was higher among unmedicated, but not antidepressant-treated, suicides. Although very few DCX-IR cells were present in the control OT, they were considerably more common in suicides and correlated with OB DCX levels. Suicides also displayed higher DCX-IR process volumes. These results support the notion that OB neurogenesis is minimal in adult humans. They further raise the possibility that the differentiation and migration of SVZ-derived neuroblasts may be altered in unmedicated suicides, leading to an accumulation of ectopically differentiating cells in the OT. Normal SVZ DCX expression among suicides receiving antidepressants suggests a potentially novel mode of action of antidepressant medication. Given the modest group sizes and rarity of DCX-IR cells assessed here, a larger-scale characterization will be required before firm conclusions can be made regarding the identity of these cells.

Highlights

Adult neurogenesis is a process involving the asymmetric division of neural progenitors to produce neuroblasts which migrate to discrete brain regions, differentiate into neurons, and integrate into existing circuits
Protein Expression in the subventricular zone (SVZ) and olfactory bulb (OB) Immunoblotting revealed that while OB expression of sex determining region Y-box 2 (Sox2) and proliferating cell nuclear antigen (PCNA) did not differ between CTRL and S groups, DCX levels were significantly higher in suicides than in controls [t(19) = −2.916, p = 0.009]
Whereas pharmacological ADT appeared to have no effect on OB DCX expression, in the SVZ antidepressants were associated with normal DCX levels

Summary

Introduction

Adult neurogenesis is a process involving the asymmetric division of neural progenitors to produce neuroblasts which migrate to discrete brain regions, differentiate into neurons, and integrate into existing circuits. Recent reports indicate that SVZderived neuroblasts may instead migrate toward the human striatum, raising the possibility that variable rates of SVZ neurogenesis may not result in any change in the number of new neurons that reach the OB (Ernst et al, 2014). Given these data, it is unclear how, and how many, adult-born neurons successfully migrate to the OB and contribute to olfactory processing. These impairments include depression-related reductions in odor detection and discrimination (Pause et al, 2001; Atanasova et al, 2008; Negoias et al, 2010), as well as reduced odor processing (Pause et al, 2003)

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