The Responsiveness of TrkB to BDNF and Antidepressant Drugs Is Differentially Regulated during Mouse Development

BackgroundPrevious studies suggest that the responsiveness of TrkB receptor to BDNF is developmentally regulated in rats. Antidepressant drugs (AD) have been shown to increase TrkB signalling in the adult rodent brain, and recent findings implicate a BDNF-independent mechanism behind this phenomenon. When administered during early postnatal life, ADs produce long-lasting biochemical and behavioural alterations that are observed in adult animals.
MethodologyWe have here examined the responsiveness of brain TrkB receptors to BDNF and ADs during early postnatal life of mouse, measured as autophosphorylation of TrkB (pTrkB).
Principal FindingsWe found that ADs fail to induce TrkB signalling before postnatal day 12 (P12) after which an adult response of TrkB to ADs was observed. Interestingly, there was a temporally inverse correlation between the appearance of the responsiveness of TrkB to systemic ADs and the marked developmental reduction of BDNF-induced TrkB in brain microslices ex vivo. Basal p-TrkB status in the brain of BDNF deficient mice was significantly reduced only during early postnatal period. Enhancing cAMP (cyclic adenosine monophosphate) signalling failed to facilitate TrkB responsiveness to BDNF. Reduced responsiveness of TrkB to BDNF was not produced by the developmental increase in the expression of dominant-negative truncated TrkB.T1 because this reduction was similarly observed in the brain microslices of trkB.T1−/− mice. Moreover, postnatal AD administration produced long-lasting behavioural alterations observable in adult mice, but the responses were different when mice were treated during the time when ADs did not (P4-9) or did (P16-21) activate TrkB.
ConclusionsWe have found that ADs induce the activation of TrkB only in mice older than 2 weeks and that responsiveness of brain microslices to BDNF is reduced during the same time period. Exposure to ADs before and after the age when ADs activate TrkB produces differential long-term behavioural responses in adult mice.

研究背景：已有研究表明，大鼠体内TrkB受体（TrkB）对脑源性神经营养因子（BDNF）的响应能力受到发育过程的调控。抗抑郁药物（AD）可增强成年啮齿类动物大脑中的TrkB信号通路活性，而近期研究提示该现象背后存在不依赖BDNF的分子机制。若在动物出生后早期阶段给予抗抑郁药物，会引发长期持续的生化与行为学改变，此类改变可在成年个体中被观测到。
方法：本研究以小鼠出生后早期阶段为研究窗口，通过检测TrkB的自身磷酸化水平（pTrkB），分析大脑TrkB受体对BDNF与抗抑郁药物的响应能力。
主要发现：研究发现，在小鼠出生后第12天（P12）之前，抗抑郁药物无法诱导TrkB信号通路激活；而在P12之后，则可观测到TrkB对抗抑郁药物的成年型响应。值得注意的是，TrkB对全身性给予的抗抑郁药物的响应能力出现的时间节点，与离体脑脑片中BDNF诱导的TrkB活性随发育显著降低的过程呈显著负相关。仅在出生后早期阶段，BDNF基因敲除小鼠大脑中的基础pTrkB水平才会显著降低。增强环磷酸腺苷（cyclic adenosine monophosphate, cAMP）信号通路活性，无法提升TrkB对BDNF的响应能力。TrkB对BDNF响应能力的降低，并非由发育过程中显性负性截短型TrkB.T1表达上调所导致——因为在TrkB.T1基因敲除（trkB.T1⁻/⁻）小鼠的脑脑片中，同样观测到了此类响应能力降低的现象。此外，出生后给予抗抑郁药物会引发成年小鼠长期持续的行为学改变，但若给药时间处于抗抑郁药物无法激活TrkB的阶段（P4-9），与处于可激活TrkB的阶段（P16-21）时，所引发的行为学响应存在显著差异。
结论：本研究证实，抗抑郁药物仅能在出生2周以上的小鼠中诱导TrkB信号通路激活，且在同一发育阶段，离体脑脑片对BDNF的响应能力出现降低。在抗抑郁药物可激活TrkB的时间节点前后给予抗抑郁药物，会在成年小鼠中引发截然不同的长期行为学响应。