Juvenile cerebral ischemia reveals age-dependent BDNF-TrkB signaling changes: Novel mechanism of recovery and therapeutic intervention
Juvenile cerebral ischemia reveals age-dependent BDNF-TrkB signaling changes: Novel mechanism of recovery and therapeutic intervention
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DOI：
10.1177/0271678x18766421
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发表时间：
2018-12-01
影响因子：
6.3
通讯作者：
Herson, Paco S.
中科院分区：
文献类型：
--
作者：
Dietz, Robert M.;Orfila, James E.;Herson, Paco S.
儿童时期的全脑缺血常常导致不良的神经系统预后，包括学习和记忆缺陷。利用我们的儿童心脏骤停/心肺复苏（CA/CPR）的新模型，我们研究了缺血诱导的认知缺陷和恢复的机制。青少年CA/CPR后7天出现记忆损伤，30天完全恢复。与成人未观察到的显著恢复一致的是，CA/CPR后7-14天海马长期增强（LTP）受损，30天恢复。这种恢复不是由于死亡神经元的替换（神经发生），而是与脑源性神经营养因子（BDNF）的表达相关，暗示BDNF是损伤和恢复的分子机制。重要的是，TrkB受体信号的延迟激活可以逆转CA/ pr诱导的LTP缺陷和记忆障碍。这些数据提供了两个新的见解：(1)与成人相比，发育过程中记忆和LTP的内源性恢复可能有助于改善儿童的神经预后；(2)bdnf增强药物加速了学龄期儿童心脏骤停的恢复。
Global ischemia in childhood often leads to poor neurologic outcomes, including learning and memory deficits. Using our novel model of childhood cardiac arrest/cardiopulmonary resuscitation (CA/CPR), we investigate the mechanism of ischemia-induced cognitive deficits and recovery. Memory is impaired seven days after juvenile CA/CPR and completely recovers by 30 days. Consistent with this remarkable recovery not observed in adults, hippocampal long-term potentiation (LTP) is impaired 7-14 days after CA/CPR, recovering by 30 days. This recovery is not due to the replacement of dead neurons (neurogenesis), but rather correlates with brain-derived neurotrophic factor (BDNF) expression, implicating BDNF as the molecular mechanism underlying impairment and recovery. Importantly, delayed activation of TrkB receptor signaling reverses CA/CPR-induced LTP deficits and memory impairments. These data provide two new insights (1) endogenous recovery of memory and LTP through development may contribute to improved neurological outcome in children compared to adults and (2) BDNF-enhancing drugs speed recovery from pediatric cardiac arrest during the critical school ages.