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Elevated expression of endogenous glial cell line‐derived neurotrophic factor impairs spatial memory performance and raises inhibitory tone in the hippocampus
European Journal of Neuroscience ( IF 3.698 ) Pub Date : 2021-01-22 , DOI: 10.1111/ejn.15126
Pepin Marshall 1 , Daniel R. Garton 2 , Tomi Taira 1, 3 , Vootele Võikar 1 , Carolina Vilenius 1 , Natalia Kulesskaya 1 , Claudio Rivera 1, 4 , Jaan‐Olle Andressoo 2, 5
Affiliation  

Parvalbumin‐positive interneurons (PV+) are a key component of inhibitory networks in the brain and are known to modulate memory and learning by shaping network activity. The mechanisms of PV+ neuron generation and maintenance are not fully understood, yet current evidence suggests that signalling via the glial cell line‐derived neurotrophic factor (GDNF) receptor GFRα1 positively modulates the migration and differentiation of PV+ interneurons in the cortex. Whether GDNF also regulates PV+ cells in the hippocampus is currently unknown. In this study, we utilized a Gdnf “hypermorph” mouse model where GDNF is overexpressed from the native gene locus, providing greatly increased spatial and temporal specificity of protein expression over established models of ectopic expression. Gdnfwt/hyper mice demonstrated impairments in long‐term memory performance in the Morris water maze test and an increase in inhibitory tone in the hippocampus measured electrophysiologically in acute brain slice preparations. Increased PV+ cell number was confirmed immunohistochemically in the hippocampus and in discrete cortical areas and an increase in epileptic seizure threshold was observed in vivo. The data consolidate prior evidence for the actions of GDNF as a regulator of PV+ cell development in the cortex and demonstrate functional effects upon network excitability via modulation of functional GABAergic signalling and under epileptic challenge.

中文翻译:

内源性神经胶质细胞源性神经营养因子的高表达会损害空间记忆性能并提高海马的抑制音

小白蛋白阳性中间神经元(PV +)是大脑抑制性网络的关键组成部分,已知通过调节网络活动来调节记忆和学习。PV +神经元的生成和维持机制尚不完全清楚,但目前的证据表明,通过神经胶质细胞系衍生的神经营养因子(GDNF)受体GFRα1发出的信号可正向调节PV +神经元在皮层中的迁移和分化。目前尚不清楚GDNF是否也调节海马中的PV +细胞。在这项研究中,我们利用了Gdnf “超形态”小鼠模型,其中GDNF从天然基因位点过表达,与已建立的异位表达模型相比,蛋白质表达的时空特异性大大提高。Gdnfwt / hyper小鼠在Morris水迷宫测试中显示长期记忆性能受损,在急性脑切片制剂中用电生理学方法测量的海马抑制音增加。通过免疫组织化学方法在海马和不连续的皮层区域确认了PV +细胞数量的增加,并且在体内观察到癫痫发作阈值的增加。数据巩固了GDNF作为皮层中PV +细胞发育调节剂的作用的先前证据,并通过调节功能性GABA能信号传导和在癫痫发作下证明了对网络兴奋性的功能作用。
更新日期:2021-01-22
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