Gallant S, Welch L, Martone P, Shalev U
Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Québec, Canada, H4B 1R6.
Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Québec, Canada, H4B 1R6.
Behav Brain Res. 2017 Jun 15;328:62-69. doi: 10.1016/j.bbr.2017.04.004. Epub 2017 Apr 6.
Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats.
Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed.
Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls.
Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia.
精神分裂症患者表现出认知功能受损以及对拟精神病药物的敏感性增加。精神分裂症的神经发育假说认为，发育中的大脑受到破坏会使神经网络易于出现持久的结构和功能异常，从而在成年期出现此类症状。鉴于谷氨酸能系统在早期大脑发育中的关键作用，我们研究了孕期长期暴露于谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801是否会在幼年和成年大鼠中诱发类似精神分裂症的行为和神经化学变化。
在妊娠第7至19天，给怀孕的Long-Evans大鼠皮下注射生理盐水或MK-801（0.1mg/kg）。分别使用新颖物体偏好任务和基于迷宫的转换程序，对雄性后代的物体识别记忆和认知灵活性进行评估。还评估了急性苯丙胺和MK-801的运动激活作用。
成年但非幼年的产前MK-801处理大鼠在延迟90分钟后未能表现出对新颖物体的偏好，这表明物体识别记忆可能受损。此外，转换任务显示，与对照组相比，成年产前MK-801处理大鼠获取新规则的能力受损。这种缺陷似乎是由回归到先前学习的行为所驱动的。在幼年后代或成年后代接受急性苯丙胺刺激后，药物诱导的运动活动没有显著差异。出乎意料的是，与对照组相比，成年产前MK-801处理大鼠中MK-801诱导的运动活动较低。
早期发育过程中的谷氨酸传递功能障碍可能会改变成年期的行为参数，尽管这些参数似乎无法模拟精神分裂症中观察到的缺陷。
