Institute of Pharmacology and Neurosciences, Faculty of Medicine and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
Neuropsychopharmacology. 2011 Aug;36(9):1823-36. doi: 10.1038/npp.2011.64. Epub 2011 Apr 27.
Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak θ-burst stimuli and dependent on co-activation of adenosine A(2A) receptors (A(2A)R), which are more expressed in aged rats. As θ-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak θ-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80-week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A(2A)R antagonist, SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF.
长时程增强（LTP）被认为是学习和记忆的神经生理基础，它受到脑源性神经营养因子（BDNF）的促进，当 LTP 由弱θ爆发刺激引起并且依赖于腺苷 A（2A）受体（A（2A）R）的共同激活时，这种作用更为明显，而 A（2A）R 在老年大鼠中表达更为丰富。由于θ爆发刺激也有利于老年动物的 LTP，我们假设衰老过程中 LTP 的增强可能与 BDNF 神经调节的变化有关。与来自 4 或 10 至 15 周龄大鼠的切片相比，来自 36 至 38 周龄和 70 至 80 周龄大鼠的 Schaffer 侧支给予弱θ爆发刺激诱导的 CA1 LTP 幅度明显更高；这种增强不会影响认知改善，因为老年大鼠在海马依赖性学习和记忆表现方面存在损伤，这可以通过 Morris 水迷宫测试来评估。BDNF 的清除剂 TrkB-Fc 和 Trk 磷酸化抑制剂 K252a 减弱了来自 70 至 80 周龄大鼠的 LTP，但对来自 10 至 15 周龄大鼠的 LTP 没有影响。当外源性添加时，BDNF 显著增加了来自 4 周龄和 10 至 15 周龄大鼠的 LTP，但在 36 至 38 周龄或 70 至 80 周龄大鼠中并未进一步增加 LTP。外源性 BDNF 对 LTP 的影响被 A（2A）R 拮抗剂 SCH58261（7-（2-苯乙基）-5-氨基-2-（2-呋喃基）-吡唑并[4,3-e]-1,2,4-三唑[1,5-c]嘧啶）所阻止。这些结果表明，在衰老过程中观察到的更高 LTP 幅度，而不会转化为改善的空间记忆表现，是内源性 BDNF 紧张作用增加的结果。
