School of Psychology and Public Health, La Trobe University, Melbourne, Australia; Department of Pharmacology, University of Melbourne, Melbourne, 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, Australia.
Schizophr Res. 2018 Aug;198:60-67. doi: 10.1016/j.schres.2017.08.019. Epub 2017 Aug 30.
The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism results in reduced activity-dependent BDNF release and has been implicated in schizophrenia. However, effects of the polymorphism on functional dopaminergic and N-methyl-d-aspartate (NMDA) receptor-associated activity remain unclear. We used prepulse inhibition, a measure of sensorimotor gating which is disrupted in schizophrenia, and assessed the effects of acute treatment with the dopamine receptor agonist, apomorphine (APO), and the NMDA receptor antagonist, MK-801. We used adult humanized hBDNF 'knockin' mice which express either the Val/Val, Val/Met or Met/Met genotype. An interaction of BDNF with stress was modelled by chronic young-adult treatment with corticosterone (CORT). At 1 or 3mg/kg, APO had no effect in Val/Val mice but significantly reduced PPI at the 100ms inter-stimulus interval (ISI) in Val/Met and Met/Met mice. However, after CORT pretreatment, APO significantly reduced PPI in all genotypes similarly. At 0.1 or 0.25mg/kg, MK-801 significantly disrupted PPI at the 100ms ISI independent of genotype or CORT pretreatment. There were differential effects of APO and MK-801 on PPI at the 30ms ISI and startle between the genotypes, irrespective of CORT pretreatment. These results show that the BDNF Val66Met Val/Met and Met/Met genotypes are more sensitive than the Val/Val genotype to the effect of APO on PPI. A history of stress, here modelled by chronic CORT administration, increases effects of APO in Val/Val mice.
脑源性神经营养因子（BDNF）Val66Met 多态性导致活性依赖性 BDNF 释放减少，并与精神分裂症有关。然而，该多态性对功能性多巴胺能和 N-甲基-D-天冬氨酸（NMDA）受体相关活性的影响仍不清楚。我们使用了前脉冲抑制（一种用于测量感觉运动门控的方法，该方法在精神分裂症中受到破坏），并评估了多巴胺受体激动剂阿扑吗啡（APO）和 NMDA 受体拮抗剂 MK-801 急性治疗的效果。我们使用表达 Val/Val、Val/Met 或 Met/Met 基因型的成人人类化 hBDNF“敲入”小鼠。BDNF 与应激的相互作用通过慢性成年早期皮质酮（CORT）处理来模拟。在 1 或 3mg/kg 时，APO 对 Val/Val 小鼠没有影响，但在 Val/Met 和 Met/Met 小鼠中显著降低了 100ms 刺激间隔（ISI）的前脉冲抑制。然而，在 CORT 预处理后，APO 对所有基因型的 PPI 均显著降低。在 0.1 或 0.25mg/kg 时，MK-801 独立于基因型或 CORT 预处理，显著破坏了 100ms ISI 的 PPI。APO 和 MK-801 对 PPI 和 30ms ISI 之间的惊跳反应的影响在基因型之间存在差异，而与 CORT 预处理无关。这些结果表明，BDNF Val66Met Val/Met 和 Met/Met 基因型比 Val/Val 基因型对 APO 对 PPI 的影响更为敏感。应激的历史，在这里通过慢性 CORT 给药来模拟，增加了 Val/Val 小鼠中 APO 的作用。
