Lanshakov Dmitriy, Shaburova Elizaveta, Sukhareva Ekaterina, Bulygina Veta, Drozd Uliana, Larionova Irina, Gerashchenko Tatiana, Shnaider Tatiana, Denisov Evgeny V, Kalinina Tatyana
Postgenomics Neurobiology Laboratory, Institute of Cytology and Genetics, Novosibirsk, Russia.
Novosibirsk State University, Novosibirsk, Russia.
PeerJ. 2024 Nov 27;12:e18465. doi: 10.7717/peerj.18465. eCollection 2024.
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: . 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 could play a substantial role in the pathogenesis of this neurobehavioral disorder.
脑源性神经营养因子（BDNF）是一种分泌型分子，在神经细胞的存活和生长中起重要作用。BDNF会经历细胞蛋白酶介导的复杂翻译后加工过程。前体BDNF和成熟BDNF形式与大脑中的不同受体类型结合。BDNF在新生儿大脑皮层中含量丰富。新生儿期对于大脑和神经系统的正常发育至关重要。这些关键时期的紊乱会对行为和心理健康产生长期影响。在新生儿期经历不良影响的个体已表现出易患抑郁症和其他神经行为障碍的倾向。在这项研究中，我们研究了在新生儿内侧前额叶皮层（mPFC）中短暂表达（P3 - P8）无法被细胞转化酶加工的前体、成熟和突变形式的BDNF对青少年焦虑和抑郁样行为的影响。成熟BDNF（LV - BDNF）表达升高在P30时增加了焦虑和抑郁样行为。仅在表达突变BDNF（LV - pBDNF mut）后，悬尾试验中的不动时间增加。利用我们的RNA测序数据和在线可用的单细胞核RNA测序结果，我们研究了P8时新生儿mPFC中的转录组变化，这些变化是随后行为变化的基础。成熟BDNF表达导致血管周围基质细胞（PSC）中一些基因的转录反应增加： 。基于全基因组关联研究（GWAS）数据，Ptgds是与注意力缺陷多动障碍（ADHD）和双相情感障碍相关的候选基因（普约尔 - 瓜尔多等人，2021年；马林 - 门德斯等人，2012年；蒙克霍尔姆等人，2015年）。与LV - BDNF相比，LV - pBDNF mut在PSC中引起了完全相反的一组转录变化。成熟和突变形式的BDNF表达后观察到的相似行为表型以及检测到的与双相情感障碍相关的基因表明， 可能在这种神经行为障碍的发病机制中起重要作用。
