Altered prepulse inhibition of the acoustic startle response in BDNF-deficient mice in a model of early postnatal hypoxia: implications for schizophrenia
Altered prepulse inhibition of the acoustic startle response in BDNF-deficient mice in a model of early postnatal hypoxia: implications for schizophrenia
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DOI：
10.1007/s00406-018-0882-6
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发表时间：
2019-06
影响因子：
4.7
通讯作者：
J. Lima-Ojeda;A. Mallien;C. Brandwein;U. Lang;Dimitri Hefter;D. Inta
中科院分区：
文献类型：
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作者：
J. Lima-Ojeda;A. Mallien;C. Brandwein;U. Lang;Dimitri Hefter;D. Inta
脑源性神经营养因子（BDNF）是神经系统中的主要增殖剂。BDNF缺乏和围产期缺氧都是精神分裂症的遗传/环境危险因素。此外，BDNF对出生缺氧的反应降低与疾病有关。BDNF的表达受神经元活动和环境条件如缺氧的影响。因此，它可能参与急性或慢性神经元损伤的神经保护和修复机制。然而，缺氧和BDNF的相互作用还没有得到充分的理解，行为结果未知。因此，我们进行了一系列的行为测试，在一个经典的模型慢性早期出生后轻度缺氧（10%O2），已知显着损害大脑发育，在BDNF缺陷小鼠。我们发现选择性赤字的措施与感觉运动门控，即增强声惊吓反应（ASR）和减少前脉冲抑制（PPI）的ASR在BDNF缺陷的小鼠。出乎意料的是，感觉运动门控的改变仅由BDNF缺陷引起，而缺氧未能引起严重的缺陷，甚至导致BDNF缺陷小鼠的表型较温和。由于感觉运动门控缺陷存在于精神分裂症和动物模型中，我们的研究结果与BDNF参与其发病机制有关。另一方面，他们认为，围产期缺氧对长期脑异常的影响是复杂的，从保护到有害的行动，并可能严重依赖于缺氧的程度。因此，未来的研究可能会完善现有的缺氧协议，以更好地了解与精神分裂症相关的神经发育后果。
The brain-derived neurotrophic factor (BDNF) is a major proliferative agent in the nervous system. Both BDNF-deficiency and perinatal hypoxia represent genetic/environmental risk factors for schizophrenia. Moreover, a decreased BDNF response to birth hypoxia was associated with the disease. BDNF expression is influenced by neuronal activity and environmental conditions such as hypoxia. Thus, it may partake in neuroprotective and reparative mechanisms in acute or chronic neuronal insults. However, the interaction of hypoxia and BDNF is insufficiently understood and the behavioral outcome unknown. Therefore, we conducted a battery of behavioral tests in a classical model of chronic early postnatal mild hypoxia (10% O2), known to significantly impair brain development, in BDNF-deficient mice. We found selective deficits in measures associated with sensorimotor gating, namely enhanced acoustic startle response (ASR) and reduced prepulse inhibition (PPI) of ASR in BDNF-deficient mice. Unexpectedly, the alterations of sensorimotor gating were caused only by BDNF-deficiency alone, whereas hypoxia failed to evoke severe deficits and even leads to a milder phenotype in BDNF-deficient mice. As deficits in sensorimotor gating are present in schizophrenia and animal models of the disease, our results are of relevance regarding the involvement of BDNF in its pathogenesis. On the other hand, they suggest that the effect of perinatal hypoxia on long-term brain abnormalities is complex, ranging from protective to deleterious actions, and may critically depend on the degree of hypoxia. Therefore, future studies may refine existing hypoxia protocols to better understand neurodevelopmental consequences associated with schizophrenia.