1. Academic Validation
  2. Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats

Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats

  • Front Mol Neurosci. 2017 Aug 28;10:269. doi: 10.3389/fnmol.2017.00269.
Yonglu Tian 1 2 Chaojuan Yang 1 Shujiang Shang 1 Yijun Cai 3 Xiaofei Deng 4 Jian Zhang 1 Feng Shao 5 Desheng Zhu 1 Yunbo Liu 6 Guiquan Chen 7 Jing Liang 4 Qiang Sun 3 Zilong Qiu 3 Chen Zhang 1 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking UniversityBeijing, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking UniversityBeijing, China.
  • 3 CAS Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Chinese Academy of SciencesShanghai, China.
  • 4 Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of SciencesBeijing, China.
  • 5 Department of Psychology, Peking UniversityBeijing, China.
  • 6 Institute of Laboratory Animal Science, Peking Union Medical College/Chinese Academy of Medical SciencesBeijing, China.
  • 7 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing UniversityNanjing, China.
  • 8 Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking UniversityBeijing, China.
Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene that inactivate expression of the gene product, the fragile X mental retardation 1 protein (FMRP). In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology to generate Fmr1 knockout (KO) rats by disruption of the fourth exon of the Fmr1 gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the Fmr1 KO rats (Fmr1exon4-KO ). Electrophysiological analysis revealed that the theta-burst stimulation (TBS)-induced long-term potentiation (LTP) and the low-frequency stimulus (LFS)-induced long-term depression (LTD) were decreased in the hippocampal Schaffer collateral pathway of the Fmr1exon4-KO rats. Short-term plasticity, measured as the paired-pulse ratio, remained normal in the KO rats. The synaptic strength mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was also impaired. Consistent with previous reports, the Fmr1exon4-KO rats demonstrated an enhanced 3,5-dihydroxyphenylglycine (DHPG)-induced LTD in the present study, and this enhancement is insensitive to protein translation. In addition, the Fmr1exon4-KO rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the Fmr1 gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the Fmr1exon4-KO rats displayed impaired social interaction and macroorchidism, the results consistent with those observed in patients with FXS. Thus, Fmr1exon4-KO rats constitute a novel rat model of FXS that complements existing mouse models.

Keywords

FXS; hippocampus; intellectual disability; long-term plasticity; spatial learning.

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