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Genetic deletion of the 67‐kDa isoform of glutamate decarboxylase alters conditioned fear behavior in rats
FEBS Open Bio ( IF 2.6 ) Pub Date : 2020-12-15 , DOI: 10.1002/2211-5463.13065
Kazuyuki Fujihara 1, 2 , Takumi Sato 1 , Yoshiki Miyasaka 3 , Tomoji Mashimo 4 , Yuchio Yanagawa 1
Affiliation  

The GABAergic system is thought to play an important role in the control of cognition and emotion, such as fear, and is related to the pathophysiology of psychiatric disorders. For example, the expression of the 67‐kDa isoform of glutamate decarboxylase (GAD67), a GABA‐producing enzyme, is downregulated in the postmortem brains of patients with major depressive disorder and schizophrenia. However, knocking out the Gad1 gene, which encodes GAD67, is lethal in mice, and thus, the association between Gad1 and cognitive/emotional functions is unclear. We recently developed Gad1 knockout rats and found that some of them can grow into adulthood. Here, we performed fear‐conditioning tests in adult Gad1 knockout rats to assess the impact of the loss of Gad1 on fear‐related behaviors and the formation of fear memory. In a protocol assessing both cued and contextual memory, Gad1 knockout rats showed a partial antiphase pattern of freezing during training and significantly excessive freezing during the contextual test compared with wild‐type rats. However, Gad1 knockout rats did not show any synchronous increase in freezing with auditory tones in the cued test. On the other hand, in a contextual memory specialized protocol, Gad1 knockout rats exhibited comparable freezing behavior to wild‐type rats, while their fear extinction was markedly impaired. These results suggest that GABA synthesis by GAD67 has differential roles in cued and contextual fear memory.

中文翻译:

谷氨酸脱羧酶 67 kDa 异构体的基因缺失改变了大鼠的条件恐惧行为

GABA能系统被认为在控制认知和情绪(如恐惧)中起重要作用,并且与精神疾病的病理生理学有关。例如,67 kDa 的谷氨酸脱羧酶 (GAD67) 异构体(一种产生 GABA 的酶)的表达在重度抑郁症和精神分裂症患者的死后大脑中被下调。然而,敲除编码 GAD67 的Gad1基因在小鼠中是致命的,因此,Gad1与认知/情绪功能之间的关联尚不清楚。我们最近开发了Gad1基因敲除大鼠,发现其中一些可以长到成年。在这里,我们在成人Gad1中进行了恐惧条件测试敲除大鼠以评估Gad1 缺失对恐惧相关行为和恐惧记忆形成的影响。在评估提示和上下文记忆的方案中,与野生型大鼠相比, Gad1基因敲除大鼠在训练期间表现出部分反相冻结模式,在上下文测试期间表现出明显过度冻结。然而,在提示测试中, Gad1基因敲除大鼠没有表现出任何冻结与听觉音调的同步增加。另一方面,在上下文记忆专用协议中,Gad1基因敲除大鼠表现出与野生型大鼠相似的冻结行为,而它们的恐惧消退能力明显受损。这些结果表明 GAD67 合成的 GABA 在提示和上下文恐惧记忆中具有不同的作用。
更新日期:2021-02-11
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