Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (SB RAS), 10 Akad. Lavrentyeva Ave., 630090 Novosibirsk, Russia.
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9 Akad. Lavrentieva Ave., 630090 Novosibirsk, Russia.
Int J Mol Sci. 2023 Jan 4;24(2):983. doi: 10.3390/ijms24020983.
The (brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of regulatory exons and the 5-HT receptor was shown, as was an association between regulatory exons and fear-induced aggression involving genetic predisposition.
（脑源性神经营养因子）基因包含八个调节外显子（I-VIII），可与蛋白编码外显子 IX 交替拼接。只有外显子 I、II、IV 和 VI 得到了相对较好的研究。BDNF 系统和脑 5-羟色胺能系统紧密相连，并与攻击性有关。苯并戊噻嗪 TC-2153 影响这两个系统，并发挥抗攻击性作用。我们的目的是评估 TC-2153 对具有高人类攻击性（攻击性）或缺乏攻击性（温顺）的大鼠大脑中 I-IX 外显子表达和 5-羟色胺受体 mRNA 水平的影响。攻击性和温顺的成年雄性大鼠单次用载体或 10 或 20mg/kg 的 TC-2153 处理。使用实时 PCR 定量皮质、海马体、下丘脑和中脑的 mRNA。针对高攻击性或缺乏攻击性的选择性繁殖对 5-羟色胺受体和外显子的转录物产生了不同的影响，这取决于基因型（品系）和脑区。TC-2153 对 外显子的表达有全面的影响。主要趋势是在下丘脑中下调。TC-2153 增加了下丘脑 5-HT 受体 mRNA 的表达。这是首次显示 TC-2153 对调节外显子和 5-HT 受体的表达有影响，以及调节外显子与涉及遗传易感性的恐惧诱导攻击性之间存在关联。
