GDNF facilitates cognitive function recovery following neonatal surgical-induced learning and memory impairment via activation of the RET pathway and modulation of downstream effectors PKMζ and Kalirin in rats

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2024-09-11 DOI:10.1016/j.brainresbull.2024.111078

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引用次数: 0

Abstract

Objective

The aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions.

Methods

Newborn Sprague–Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (n=15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting.

Results

GDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594.

Conclusion

The effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines.

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目的本研究旨在阐明神经胶质细胞系源性神经营养因子（GDNF）改善新生儿手术干预导致的成人认知缺陷的内在机制。方法新生 Sprague-Dawley 大鼠，不分性别，在出生后第 7 天随机分为以下 7 组（n=15）：(1) 对照组（未进行麻醉、手术或任何药物干预）；(2) GDNF 组（脑室内注射 GDNF）；(3) 手术组（在 3 % 七氟醚麻醉下进行右颈动脉暴露）；(4）手术加 GDNF 组；（5）手术加 GDNF 和 II 型 JAK 抑制剂 NVP-BBT594（BBT594）组（腹腔注射 BBT594）；（6）BBT 组；以及（7）手术加 BBT 组。从出生后第 33 天开始，所有大鼠均接受巴恩斯迷宫和恐惧条件反射测试，然后在七氟醚麻醉下斩首，进行后续分析。左侧大脑半球进行高尔基染色，右侧大脑半球用于提取海马蛋白，通过Western印迹法评估蛋白激酶Mζ（PKMζ）和Kalirin的表达。值得注意的是，在服用RET抑制剂BBT594后，GDNF的所有这些改善作用均被逆转。结论 GDNF 对手术干预引起的学习和记忆损伤的有效影响似乎是通过 RET 途径介导的。此外，GDNF可能通过上调PKMζ和Kalirin的表达来发挥其影响，从而促进树突和树突棘的发育。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.

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