Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201-0413.
J Neurosci. 2014 Apr 23;34(17):6057-64. doi: 10.1523/JNEUROSCI.4980-13.2014.
Brain-derived neurotrophic factor (BDNF) regulates synaptic activity and behavioral flexibility, and reduction of BDNF strongly predicts psychiatric disorders and cognitive dysfunction. Restoration of BDNF-dependent activity could alleviate these impairments, but BDNF has limited clinical utility due to its pharmacokinetics. Here we demonstrate that activation of a primary BDNF target, the tropomyosin-related kinase B (TrkB) receptor, enhances the amplitude and prolongs the decay kinetics of N-methyl-d-aspartate receptor (NMDAR) currents in male rat infralimbic prefrontal pyramidal neurons. Moreover, these effects were prevented and reversed by blockade of NMDARs containing the GluN2B subunit. Our results show that this signaling cascade bidirectionally regulates extinction of a cocaine-induced conditioned place preference (CPP), a task that requires behavioral flexibility. Blockade of infralimbic TrkB receptors or GluN2B-containing NMDARs disrupted consolidation of extinction of the CPP. In contrast, extinction was strengthened by potentiation of TrkB receptor activity with infralimbic infusions of BDNF or systemic injections of 7,8 dihydroxyflavone (7,8DHF), the newly synthesized TrkB receptor agonist. The 7,8DHF-induced enhancement of extinction was prevented by infralimbic infusions of a GluN2B-specific receptor antagonist, demonstrating that TrkB receptor activation enhances extinction of cocaine-CPP via GluN2B-containing NMDARs. Together, infralimbic TrkB receptor activation strengthens GluN2B-containing NMDAR currents to support extinction learning. TrkB receptor agonists would therefore be useful as pharmacological adjuncts for extinction-based therapies for treatment of psychiatric disorders associated with reduced BDNF activity.
脑源性神经营养因子（BDNF）调节突触活动和行为灵活性，BDNF 的减少强烈预测精神疾病和认知功能障碍。恢复 BDNF 依赖性活动可以减轻这些损伤，但由于其药代动力学，BDNF 的临床应用有限。我们证明，激活 BDNF 的主要靶标，原肌球蛋白相关激酶 B（TrkB）受体，可增强雄性大鼠边缘下前额叶皮质锥体神经元中 N-甲基-D-天冬氨酸受体（NMDAR）电流的幅度并延长其衰减动力学。此外，这些作用被 NMDAR 中包含的 GluN2B 亚基的阻断所阻止和逆转。我们的结果表明，这种信号级联双向调节可卡因诱导的条件性位置偏好（CPP）的消退，CPP 是一种需要行为灵活性的任务。阻断边缘下 TrkB 受体或包含 GluN2B 的 NMDAR 破坏了 CPP 的消退巩固。相比之下，通过边缘下脑啡肽受体的 BDNF 输注或全身注射新合成的 TrkB 受体激动剂 7,8-二羟基黄酮（7,8DHF）增强 TrkB 受体活性可增强消退。7,8DHF 诱导的消退增强被边缘下脑啡肽受体的 GluN2B 特异性受体拮抗剂所阻止，表明 TrkB 受体激活通过 GluN2B 包含的 NMDAR 增强可卡因 CPP 的消退。总之，边缘下 TrkB 受体的激活增强了 GluN2B 包含的 NMDAR 电流，以支持消退学习。因此，TrkB 受体激动剂将作为基于消退的治疗与 BDNF 活性降低相关的精神疾病的药理学辅助手段非常有用。
