BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice
BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice
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DOI：
10.1111/j.1471-4159.2007.05149.x
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发表时间：
2008-04-01
影响因子：
4.7
通讯作者：
Valverde, Olga
中科院分区：
文献类型：
--
作者：
Aso, Ester;Ozaita, Andres;Valverde, Olga
应激可通过破坏促进神经元可塑性的神经营养因子的表达而引起海马神经元的损伤和萎缩。内源性大麻素系统代表了在细胞和情绪水平上参与神经保护的生理底物。CB 1受体的缺乏改变了神经元的可塑性，并在小鼠中产生了焦虑样表型。在本研究中，CB 1基因敲除小鼠表现出增强的应激反应所揭示的增加绝望行为和皮质酮水平显示在悬尾试验和海马脑源性神经营养因子（BDNF）水平下降。有趣的是，在海马中局部给予BDNF逆转了CB 1基因敲除小鼠增加的绝望行为，证实了BDNF在这些突变体的情感障碍中发挥的关键作用。神经营养缺乏似乎是特定的BDNF的神经生长因子和NT-3，两个额外的神经营养因子的水平没有发现差异。此外，BDNF损伤与其特异性酪氨酸激酶受体的活性或转录因子cAMP反应元件结合的活性无关。这些结果表明，CB 1受体的缺乏引起对应激的反应增强和神经元可塑性的缺陷，通过降低海马中的BDNF水平，导致对情绪障碍的反应受损。
Stress can cause damage and atrophy of neurons in the hippocampus by deregulating the expression of neurotrophic factors that promote neuronal plasticity. The endocannabinoid system represents a physiological substrate involved in neuroprotection at both cellular and emotional levels. The lack of CB1 receptor alters neuronal plasticity and originates an anxiety-like phenotype in mice. In the present study, CB1 knockout mice exhibited an augmented response to stress revealed by the increased despair behavior and corticosterone levels showed in the tail suspension test and decreased brain derived neurotrophic factor (BDNF) levels in the hippocampus. Interestingly, local administration of BDNF in the hippocampus reversed the increased despair behavior of CB1 knockout mice, confirming the crucial role played by BDNF on the emotional impairment of these mutants. The neurotrophic deficiency seems to be specific for BDNF as no differences were found in the levels of nerve growth factor and NT-3, two additional neurotrophic factors. Moreover, BDNF impairment is not related to the activity of its specific tyrosine kinase receptor or the activity of the transcription factor cAMP responsive element binding. These results suggest that the lack of CB1 receptor originates an enhanced response to stress and deficiency in neuronal plasticity by decreasing BDNF levels in the hippocampus that lead to impairment in the responses to emotional disturbances.