van den Buuse Maarten, Biel Davina, Radscheit Kathrin
School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia; Department of Pharmacology, University of Melbourne, Victoria, Australia; The College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia.
School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia; Institute of Psychology, University of Luebeck, Luebeck, Germany.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 3;75:192-198. doi: 10.1016/j.pnpbp.2017.02.009. Epub 2017 Feb 10.
Several studies have suggested a role of BDNF in the development of schizophrenia. For example, post-mortem studies have shown significantly reduced levels of BDNF protein expression in the brain of schizophrenia patients. We investigated the relationship between reduced levels of BDNF in the brain and the regulation of prepulse inhibition (PPI), a behavioral endophenotype of schizophrenia. We used BDNF heterozygous mutant rats which display a 50% decrease of mature BDNF protein levels. Previously, we observed normal baseline PPI and responses to the dopamine D1/D2 receptor agonist, apomorphine, in these rats. Here, we focused on the effects of the NMDA receptor antagonist, MK-801, its interaction with mGluR2/3 and mGluR5 receptors, and the PPI response to serotonergic drugs. MK-801 administration caused a dose-dependent reduction of PPI and increase of startle amplitudes. Baseline PPI and the effect of 0.02-0.1mg/kg of MK-801 were not significantly altered in male or female BDNF heterozygous rats, although the MK-801-induced increase in startle levels was reduced. Co-treatment with the mGluR2/3 agonist, LY379,268, or the mGluR5 antagonist, MPEP, did not alter the effect of MK-801 on PPI in controls or BDNF mutant rats. Treatment with the serotonin-1A receptor agonist, 8-OH-DPAT, the serotonin-2A receptor agonist, DOI, or the serotonin releaser, fenfluramine, induced differential effects on PPI and startle but these effects were not different between the genotypes. These results show that a significant decrease of BDNF protein expression does not lead to reduced PPI at baseline or changes in the regulation of PPI via NMDA receptors or serotonergic mechanisms. These findings in a genetic rat model of BDNF deficiency do not support a role for similar reductions of BDNF levels in schizophrenia in the disruption of PPI, widely reported as an endophenotype of the illness. The potential implications of these results for our understanding of changes in PPI and BDNF expression in schizophrenia are discussed.
多项研究表明脑源性神经营养因子（BDNF）在精神分裂症的发病过程中发挥作用。例如，尸检研究显示，精神分裂症患者大脑中BDNF蛋白表达水平显著降低。我们研究了大脑中BDNF水平降低与前脉冲抑制（PPI）调节之间的关系，PPI是精神分裂症的一种行为内表型。我们使用了BDNF杂合突变大鼠，其成熟BDNF蛋白水平降低了50%。此前，我们观察到这些大鼠的基线PPI以及对多巴胺D1/D2受体激动剂阿扑吗啡的反应均正常。在此，我们重点研究了N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801的作用、其与代谢型谷氨酸受体2/3（mGluR2/3）和代谢型谷氨酸受体5（mGluR5）的相互作用，以及PPI对血清素能药物的反应。给予MK-801会导致PPI剂量依赖性降低以及惊跳幅度增加。在雄性或雌性BDNF杂合大鼠中，基线PPI以及0.02 - 0.1mg/kg的MK-8所产生的效应均未发生显著改变，尽管MK-801诱导的惊跳水平增加有所降低。与mGluR2/3激动剂LY379,268或mGluR5拮抗剂MPEP联合治疗，并未改变MK-801对对照组或BDNF突变大鼠PPI的影响。给予5-羟色胺-1A（5-HT1A）受体激动剂8-羟基二苯丙胺（8-OH-DPAT）、5-羟色胺-2A（5-HT2A）受体激动剂DOI或5-羟色胺释放剂芬氟拉明，会对PPI和惊跳产生不同的影响，但这些影响在不同基因型之间并无差异。这些结果表明，BDNF蛋白表达的显著降低并不会导致基线PPI降低，也不会通过NMDA受体或血清素能机制改变PPI的调节。在BDNF缺乏的基因大鼠模型中的这些发现并不支持在精神分裂症中BDNF水平类似降低在PPI破坏中所起的作用，PPI破坏广泛报道为该疾病的一种内表型。我们讨论了这些结果对于我们理解精神分裂症中PPI和BDNF表达变化的潜在意义。
