Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.
Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
Neuropsychopharmacology. 2023 Jun;48(7):1021-1030. doi: 10.1038/s41386-023-01562-y. Epub 2023 Mar 21.
Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin-positive (PV) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV interneurons (PV-TrkB hCKO) in IntelliCage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV interneurons. In addition, hippocampal long-term potentiation was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV interneurons, and here we show that TrkB expression in PV interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.
类似关键期的可塑性（i 可塑性）可以通过多种干预措施在成年大脑中重新建立，包括药物和光遗传学修饰。我们已经证明，i 可塑性与最佳训练相结合可以改善与神经精神障碍相关的行为。在这种情况下，激活脑源性神经营养因子（BDNF）的受体 TrkB 在 Parvalbumin 阳性（PV）中间神经元中在皮质网络变化中起着关键作用。然而，尚不清楚 TrkB 在 PV 中间神经元中的激活是否对其他与可塑性相关的行为很重要，特别是学习和记忆。在这里，我们使用在 IntelliCage 和恐惧消除范式中具有 PV 中间神经元异源条件性 TrkB 缺失（PV-TrkB hCKO）的小鼠，表明氟西汀（一种广泛开处方的抗抑郁药，已知可促进 TrkB 的激活）的慢性治疗增强了空间和恐惧记忆中的行为灵活性，这在很大程度上取决于 PV 中间神经元中 TrkB 受体的表达。此外，氟西汀在野生型小鼠中慢性治疗增强了海马长时程增强，但在 PV-TrkB hCKO 小鼠中则没有。氟西汀治疗后对 PV 中间神经元的转录组分析表明，突触形成的内在变化和参与周围神经网形成的酶的下调。一致地，免疫组织化学显示氟西汀处理改变了 PV 表达并减少了 PV 中间神经元中的 PNNs，并且我们在这里表明，PV 中间神经元中的 TrkB 表达是这些效应所必需的。总之，我们的研究结果为成年期类似关键期的可塑性的诱导提供了分子和网络机制。
