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BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects

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Abstract

Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.

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Data availability

The data supporting the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by the São Paulo Research Foundation. We thank the University of São Paulo for all its support and the team of researchers, patients and volunteers that participated in this long-term study. The authors report no biomedical financial interests or potential conflicts of interest.

Funding

The Sao Paulo Research Foundation (FAPESP) financed this study (2012/23796-2 and 2010/12286-8).

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Authors and Affiliations

  1. Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil

    Estêvão Scotti-Muzzi & Márcio Gerhardt Soeiro-de-Souza

  2. Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), São Paulo, Brazil

    Thais Chile & Homero Vallada

  3. Laboratory of Magnetic Resonance in Neuroradiology LIM44, Department and Institute of Radiology, School of Medicine, University of São Paulo (FMUSP), São Paulo, Brazil

    Maria Concepción Garcia Otaduy

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  1. Estêvão Scotti-Muzzi
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Conception and study design (ES-M, MCGO, MGS-S), data collection or acquisition (E-SM, TC, HV, MCGO, MGS-S), statistical analysis (ES-M and MGS-S), interpretation of results (ES-M and MGS-S), drafting the manuscript or revising it critically for important intellectual content (ES-M, MCGO, MGS-S), and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the study (E-SM, TC, HV, MCGO, MGS-S).

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Scotti-Muzzi, E., Chile, T., Vallada, H. et al. BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects. Brain Imaging and Behavior 17, 282–293 (2023). https://doi.org/10.1007/s11682-023-00757-7

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