RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
Eur Arch Psychiatry Clin Neurosci. 2019 Jun;269(4):439-447. doi: 10.1007/s00406-018-0882-6. Epub 2018 Feb 16.
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% O), 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.
脑源性神经营养因子（BDNF）是神经系统中的主要增殖剂。BDNF 缺乏和围产期缺氧均代表精神分裂症的遗传/环境风险因素。此外，出生时缺氧对 BDNF 反应的降低与该疾病有关。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 的相互作用尚未得到充分理解，其行为结果也未知。因此，我们在经典的慢性早期产后轻度缺氧（10%O）模型中，对 BDNF 缺陷型小鼠进行了一系列行为测试，该模型已知会严重损害大脑发育。我们发现与感觉运动门控相关的测量值存在选择性缺陷，即 BDNF 缺陷型小鼠的听觉起始反应（ASR）增强和 ASR 的前脉冲抑制（PPI）降低。出乎意料的是，感觉运动门控的改变仅由 BDNF 缺陷型引起，而缺氧未能引起严重缺陷，甚至在 BDNF 缺陷型小鼠中导致更轻微的表型。由于感觉运动门控缺陷存在于精神分裂症和该疾病的动物模型中，我们的结果与 BDNF 参与其发病机制有关。另一方面，它们表明围产期缺氧对长期大脑异常的影响是复杂的，从保护作用到有害作用，并且可能严重依赖于缺氧的程度。因此，未来的研究可能会改进现有的缺氧方案，以更好地理解与精神分裂症相关的神经发育后果。
