Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

被引:212
作者
Berghuis, P
Dobszay, MB
Wang, XY
Spano, S
Ledda, F
Sousa, KM
Schulte, G
Ernfors, P
Mackie, K
Paratcha, G
Hurd, YL
Harkany, T
机构
[1] Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden
[2] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden
[3] Karolinska Univ Hosp, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden
[4] Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA
[5] Univ Washington, Dept Physiol, Seattle, WA 98195 USA
[6] Univ Washington, Dept Biophys, Seattle, WA 98195 USA
关键词
corticogenesis; drug abuse; neurotrophin;
D O I
10.1073/pnas.0509494102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:19115 / 19120
页数:6
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