Zhao Mingrui, Li Dan, Shimazu Kazuhiro, Zhou Yong-Xing, Lu Bai, Deng Chu-Xia
Section on Neural Development and Plasticity, Laboratory of Cellular & Synaptic Neurophysiology, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA.
Biol Psychiatry. 2007 Sep 1;62(5):381-90. doi: 10.1016/j.biopsych.2006.10.019. Epub 2007 Jan 18.
Although substantial evidence supports the view that adult neurogenesis is involved in learning and memory, how newly generated neurons contribute to the cognitive process remains unknown. Fibroblast growth factor 2 (FGF-2) is known to stimulate the proliferation of neuronal progenitor cells (NPCs) in adult brain. Using conditional knockout mice that lack brain expression of FGFR1, a major receptor for FGF-2, we have investigated the role of adult neurogenesis in hippocampal synaptic plasticity and learning and memory.
The Fgfr1 conditional knockout mice were generated by crossing the Fgfr1-null line, the Fgfr1-flox line, and the Nestin-Cre transgenic mice. Bromodeoxyuridine (BrdU) labeling, slice electrophysiology, and Morris Water Maze experiments were performed with the Fgfr1 conditional mutant mice.
Bromodeoxyuridine labeling experiments demonstrate that FGFR1 is required for the proliferation of NPCs as well as generation of new neurons in the adult dentate gyrus (DG). Moreover, deficits in neurogenesis in Fgfr1 mutant mice are accompanied by a severe impairment of long-term potentiation (LTP) at the medial perforant path (MPP)-granule neuron synapses in the hippocampal dentate. Moreover, the Fgfr1 mutant mice exhibit significant deficits in memory consolidation but not spatial learning.
Our study suggests a critical role of FGFR1 in adult neurogenesis in vivo, provides a potential link between proliferative neurogenesis and dentate LTP, and raises the possibility that adult neurogenesis might contribute to memory consolidation.
尽管大量证据支持成体神经发生参与学习和记忆这一观点，但新生神经元如何促进认知过程仍不清楚。已知成纤维细胞生长因子2（FGF - 2）可刺激成年大脑中神经元祖细胞（NPCs）的增殖。我们利用条件性敲除小鼠（其大脑缺乏FGF - 2的主要受体FGFR1的表达），研究了成体神经发生在海马突触可塑性以及学习和记忆中的作用。
通过将Fgfr1基因敲除品系、Fgfr1基因条件性敲除品系和巢蛋白 - Cre转基因小鼠杂交，获得Fgfr1条件性敲除小鼠。对Fgfr1条件性突变小鼠进行溴脱氧尿苷（BrdU）标记、脑片电生理学和莫里斯水迷宫实验。
溴脱氧尿苷标记实验表明，FGFR1是成年齿状回（DG）中NPCs增殖以及新神经元产生所必需的。此外，Fgfr1突变小鼠的神经发生缺陷伴随着海马齿状回内侧穿通通路（MPP）-颗粒神经元突触处长期增强（LTP）的严重受损。而且，Fgfr1突变小鼠在记忆巩固方面表现出显著缺陷，但在空间学习方面没有。
我们的研究表明FGFR1在体内成体神经发生中起关键作用，为增殖性神经发生与齿状回LTP之间提供了潜在联系，并提出成体神经发生可能有助于记忆巩固的可能性。
