Garcia C, Chen M J, Garza A A, Cotman C W, Russo-Neustadt A
Department of Biological Sciences, California State University, 5151 State University Drive, 90032, Los Angeles, CA, USA.
Neuroscience. 2003;119(3):721-32. doi: 10.1016/s0306-4522(03)00192-1.
Previous studies have shown that hippocampal brain-derived neurotrophic factor (BDNF) mRNA levels are significantly increased in rats allowed free access to exercise wheels and/or administered antidepressant medications. Enhancement of BDNF may be crucial for the clinical effect of antidepressant interventions. Since increased function of the noradrenergic and/or serotonergic systems is thought to be an important initial mechanism of antidepressant medications, we sought to test the hypothesis that noradrenergic or serotonergic function is essential for the increased BDNF transcription occurring with exercise. In addition, individual transcript variants of BDNF were examined, as evidence exists they are differentially regulated by discrete interventions, and are expressed in distinct sub-regions of the hippocampus. The neurotransmitter system-specific neurotoxins p-chloroamphetamine (serotonergic) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (noradrenergic) were administered to rats prior to commencing voluntary wheel-running activity. In situ hybridization experiments revealed an absence of exercise-induced full-length BDNF mRNA elevations in the hippocampi of noradrenergic-lesioned rats. In addition, the striking elevation of the exon I transcript in the dentate gyrus was removed with this noradrenergic lesion. In contrast, other transcript variants (exons II and III) were elevated in several hippocampal regions as a result of this lesion. In serotonin-lesioned rats, the significant increases in full-length BDNF, exon I and exon II mRNA levels were sustained without alteration (with the exception of exon IV in the cornus ammonis subregion 4, CA4). Overall, these results indicate that an intact noradrenergic system may be crucial for the observed ability of exercise to enhance full-length and exon I hippocampal BDNF mRNA expression. In addition, these results suggest that the promoter linked to exon I may provide a major regulatory point for BDNF mRNA expression in the dentate gyrus. Elevations of other exons, such as II and III, may require the activation of separate neurotransmitter systems and intracellular pathways.
先前的研究表明，在可自由使用运动轮和/或服用抗抑郁药物的大鼠中，海马脑源性神经营养因子（BDNF）的mRNA水平显著升高。BDNF的增强可能对抗抑郁干预的临床效果至关重要。由于去甲肾上腺素能和/或5-羟色胺能系统功能增强被认为是抗抑郁药物的重要初始机制，我们试图验证以下假设：去甲肾上腺素能或5-羟色胺能功能对于运动时BDNF转录增加至关重要。此外，还检测了BDNF的各个转录变体，因为有证据表明它们受到不同干预的差异调节，并在海马的不同亚区域表达。在开始自愿轮转运动之前，给大鼠注射了神经递质系统特异性神经毒素对氯苯丙胺（5-羟色胺能）和N-（2-氯乙基）-N-乙基-2-溴苄胺（去甲肾上腺素能）。原位杂交实验显示，去甲肾上腺素能损伤大鼠的海马中不存在运动诱导的全长BDNF mRNA升高。此外，齿状回中外显子I转录本的显著升高因这种去甲肾上腺素能损伤而消除。相比之下，由于这种损伤，其他转录变体（外显子II和III）在几个海马区域升高。在5-羟色胺能损伤的大鼠中，全长BDNF、外显子I和外显子II mRNA水平的显著增加得以维持且无变化（海马角4区，CA4的外显子IV除外）。总体而言，这些结果表明，完整的去甲肾上腺素能系统对于观察到的运动增强全长和外显子I海马BDNF mRNA表达的能力可能至关重要。此外，这些结果表明，与外显子I相关的启动子可能为齿状回中BDNF mRNA表达提供主要调节点。其他外显子（如II和III）的升高可能需要激活单独的神经递质系统和细胞内途径。
