Polygenic burden associated to oligodendrocyte precursor cells and radial glia influences the hippocampal volume changes induced by aerobic exercise in schizophrenia patients

Sergi Papiol,Thomas Wobrock,Berend Malchow,Andrea Schmitt,Alkomiet Hasan,Thomas Schneider-Axmann,Peter Falkai,Heike Bickeböller,Ludovico Cantuti-Castelvetri,Florian Raabe,Mikael Simons,Franziska Degenhardt,Moritz J Rossner,Daniel Keeser

doi:10.1038/s41398-019-0618-z

Abstract

Hippocampal volume decrease is a structural hallmark of schizophrenia (SCZ), and convergent evidence from postmortem and imaging studies suggests that it may be explained by changes in the cytoarchitecture of the cornu ammonis 4 (CA4) and dentate gyrus (DG) subfields. Increasing evidence indicates that aerobic exercise increases hippocampal volume in CA subfields and improves cognition in SCZ patients. Previous studies showed that the effects of exercise on the hippocampus might be connected to the polygenic burden of SCZ risk variants. However, little is known about cell type-specific genetic contributions to these structural changes. In this secondary analysis, we evaluated the modulatory role of cell type-specific SCZ polygenic risk scores (PRS) on volume changes in the CA1, CA2/3, and CA4/DG subfields over time. We studied 20 multi-episode SCZ patients and 23 healthy controls who performed aerobic exercise, and 21 multi-episode SCZ patients allocated to a control intervention (table soccer) for 3 months. Magnetic resonance imaging-based assessments were performed with FreeSurfer at baseline and after 3 months. The analyses showed that the polygenic burden associated with oligodendrocyte precursor cells (OPC) and radial glia (RG) significantly influenced the volume changes between baseline and 3 months in the CA4/DG subfield in SCZ patients performing aerobic exercise. A higher OPC- or RG-associated genetic risk burden was associated with a less pronounced volume increase or even a decrease in CA4/DG during the exercise intervention. We hypothesize that SCZ cell type-specific polygenic risk modulates the aerobic exercise-induced neuroplastic processes in the hippocampus.

Highlights

Hippocampal volume decrease has been consistently reported in first- and multi-episode schizophrenia (SCZ)
Given the previous postmortem evidence of decreased oligodendrocyte or oligodendrocyte precursor cells (OPC) numbers in hippocampal subfields in SCZ33,34, our analysis focused on the polygenic burden associated with different stages in the development of oligodendrocytes[57,58], i.e., radial glia (RG) (PRSRad), OPCs (PRSOPC), and mature oligodendrocytes (PRSOli)
Our aim was to investigate whether cell type-specific SCZ polygenic risk scores (PRS) related to RG, OPCs, or mature oligodendrocytes are associated with volume changes in CA1, CA2/3, and cornu ammonis 4 (CA4)/ dentate gyrus (DG) subfields in multi-episode SCZ patients and healthy controls after 3 months of aerobic exercise

Summary

Introduction

Hippocampal volume decrease has been consistently reported in first- and multi-episode schizophrenia (SCZ) (e.g., refs. 1–4). Studies in the general population reported the beneficial effects of physical activity on cognitive performance and brain structure and function[19,20,21], and two recent meta-analyses of these studies provided remarkable evidence that aerobic. Papiol et al Translational Psychiatry (2019)9:284 exercise, including moderate-intensity continuous training, increases hippocampal volumes[22,23]. These results suggest that neuroplastic processes in this brain region could drive symptom improvement in SCZ patients. The first study to investigate the effects of aerobic exercise on brain structure in SCZ was performed in a small sample of multi-episode patients and reported an increase in hippocampal volume after 3 months of aerobic endurance training[24]. The type, intensity, and duration of the exercise intervention may explain the differences in the results of the aforementioned studies, at least in part[25,26,27]

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