TY - JOUR

T1 - Transiently elevated expression of different forms of brain-derived neurotrophic factor in the neonatal medial prefrontal cortex affected anxiety and depressive-like behaviors in adolescence

AU - Lanshakov, Dmitriy

AU - Shaburova, Elizaveta

AU - Sukhareva, Ekaterina

AU - Bulygina, Veta

AU - Drozd, Uliana

AU - Larionova, Irina

AU - Gerashchenko, Tatiana

AU - Shnaider, Tatiana

AU - Denisov, Evgeny V.

AU - Kalinina, Tatyana

N1 - RNA sequencing was carried out using the equipment of the Core Facility \u2018\u2018Medical Genomics\u2019\u2019 (Tomsk NRMC) and the Tomsk Regional Common Use Center. Confocal images were acquired at the Institute of Cytology and Genetics Microscopy Facility. Bioinformatics analysis was carried out at the Information and Computing Center of Novosibirsk State University. Lentivirus production and RNAseq was funded through the Russian Science Foundation grant No. 24-25-00154. Animal care was funded through a Ministry of Education grant No. FWNR-2022-0002. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The following grant information was disclosed by the authors: Russian Science Foundation: No. 24-25-00154. Ministry of Education: FWNR-2022-0002. Lentivirus production and RNAseq was funded through the Russian Science Foundation grant No. 24-25-00154. Animal care was funded through a Ministry of Education grant No. FWNR-2022-0002. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The following grant information was disclosed by the authors: Russian Science Foundation: No. 24-25-00154. Ministry of Education: FWNR-2022-0002.

PY - 2024

Y1 - 2024

N2 - Brain-derived neurotrophic factor (BDNF) is a secreted molecule that plays an important role in the survival and growth of nerve cells. BDNF undergoes complex post-translational processing with cellular proteases. Pro- and mature BDNF forms bind to different receptor types in the brain. BDNF is prominent in the neonatal cerebral cortex. The neonatal period is critical for the proper development of the brain and nervous system. Disruptions in these critical periods can have long-lasting effects on behavior and mental health. Individuals who experience adverse effects in the neonatal period have demonstrated a predisposition to depression and other neurobehavioral disorders. In this work we studied the influence of transient expression (P3–P8) elevation of pro-, mature and mutant forms of BDNF that could not be processed with cellular convertases in the neonatal medial prefrontal cortex (mPFC) on anxiety and depressive-like behavior in adolescents. Elevated expression of mature BDNF (LV-BDNF) increased anxiety and depressive-like behavior at P30. Only immobility in the tail suspension test was increased after expression of mutant BDNF (LV-pBDNF mut). Using our RNA-seq data and available online sn-RNAseq results, we investigated transcriptomic changes in the neonatal mPFC at P8 that underlie subsequent behavioral changes. Mature BDNF expression caused an increased transcriptional response in perivascular stromal cells (PSC) with such genes: Ptgds, Slc6a13, Slc22a6, Bnc2, Slc13a4, Aldh1a2. Based on GWAS data, Ptgds is a candidate gene associated with ADHD and bipolar disorder Pujol-Gualdo et al. (2021); Marín-Méndez et al. (2012); Munkholm et al. (2015). LV-pBDNF mut caused a complete opposite set of transcriptional changes in the PSC compared to LV-BDNF. The observed similar behavioral phenotype after expression of mature and mutant forms of BDNF together with the detected genes related to bipolar disorder underpinned that Bdnf could play a substantial role in the pathogenesis of this neurobehavioral disorder.

AB - Brain-derived neurotrophic factor (BDNF) is a secreted molecule that plays an important role in the survival and growth of nerve cells. BDNF undergoes complex post-translational processing with cellular proteases. Pro- and mature BDNF forms bind to different receptor types in the brain. BDNF is prominent in the neonatal cerebral cortex. The neonatal period is critical for the proper development of the brain and nervous system. Disruptions in these critical periods can have long-lasting effects on behavior and mental health. Individuals who experience adverse effects in the neonatal period have demonstrated a predisposition to depression and other neurobehavioral disorders. In this work we studied the influence of transient expression (P3–P8) elevation of pro-, mature and mutant forms of BDNF that could not be processed with cellular convertases in the neonatal medial prefrontal cortex (mPFC) on anxiety and depressive-like behavior in adolescents. Elevated expression of mature BDNF (LV-BDNF) increased anxiety and depressive-like behavior at P30. Only immobility in the tail suspension test was increased after expression of mutant BDNF (LV-pBDNF mut). Using our RNA-seq data and available online sn-RNAseq results, we investigated transcriptomic changes in the neonatal mPFC at P8 that underlie subsequent behavioral changes. Mature BDNF expression caused an increased transcriptional response in perivascular stromal cells (PSC) with such genes: Ptgds, Slc6a13, Slc22a6, Bnc2, Slc13a4, Aldh1a2. Based on GWAS data, Ptgds is a candidate gene associated with ADHD and bipolar disorder Pujol-Gualdo et al. (2021); Marín-Méndez et al. (2012); Munkholm et al. (2015). LV-pBDNF mut caused a complete opposite set of transcriptional changes in the PSC compared to LV-BDNF. The observed similar behavioral phenotype after expression of mature and mutant forms of BDNF together with the detected genes related to bipolar disorder underpinned that Bdnf could play a substantial role in the pathogenesis of this neurobehavioral disorder.

KW - Anxiety

KW - Depression

KW - Juvenile period

KW - Neonatal period

KW - Prefrontal cortex

KW - RNAseq

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85210738253&origin=inward&txGid=7cc7347805b42e322bc67fd2d6f12cad

UR - https://www.mendeley.com/catalogue/302900ea-bd3d-3cf6-a944-eae28b1ff447/

U2 - 10.7717/peerj.18465

DO - 10.7717/peerj.18465

M3 - Article

C2 - 39619203

VL - 12

JO - PeerJ

JF - PeerJ

SN - 2167-8359

IS - 11

M1 - e18465

ER -