Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor
Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor
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DOI：
10.1073/pnas.0509494102
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发表时间：
2005-12-27
影响因子：
11.1
通讯作者：
Harkany, T
中科院分区：
文献类型：
--
作者：
Berghuis, P;Dobszay, MB;Harkany, T
在子宫内暴露于δ（9）-四氢大麻酚（δ（9）-THC），大麻的活性成分，诱导认知缺陷持续到成年。虽然突触结构和可塑性的变化可能是Delta（9）-THC诱导的认知障碍的基础，但Delta（9）-THC相关发育缺陷的神经元基础仍然未知。使用Boyden室试验，我们表明，激动剂刺激CB，大麻素受体（CB 1 R）胆囊收缩素表达的中间神经元诱导趋化性，这是添加剂与脑源性神经营养因子（BDNF）诱导的中间神经元迁移。我们发现，Src激酶依赖的TrkB受体反式激活介导的内源性大麻素（eCB）诱导的趋化性在BDNF的情况下。同时，eCB抑制BDNF依赖的中间神经元的形态发生，这种抑制被Src激酶抑制在体外消除。由于持续的产前Delta（9）-THC刺激CB（1）Rs选择性增加体内海马中胆囊收缩素表达中间神经元的密度，我们得出结论，产前CB（1）R活性控制皮质生成期间中间神经元的适当放置和整合。此外，eCB使用TrkB受体依赖性信号通路来调节亚型选择性中间神经元迁移和特化。
In utero exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Delta(9)-THC-induced cognitive impairments, the neuronal basis of Delta(9)-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB, cannabinoid receptor (CB1R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal Delta(9)-THC stimulation of CB(1)Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB1R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.