AUTHOR=Tian Yonglu , Yang Chaojuan , Shang Shujiang , Cai Yijun , Deng Xiaofei , Zhang Jian , Shao Feng , Zhu Desheng , Liu Yunbo , Chen Guiquan , Liang Jing , Sun Qiang , Qiu Zilong , Zhang Chen 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=10

YEAR=2017

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00269

DOI=10.3389/fnmol.2017.00269

ISSN=1662-5099

ABSTRACT=<p>Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the <italic>FMR1</italic> 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 <italic>Fmr1</italic> knockout (KO) rats by disruption of the fourth exon of the <italic>Fmr1</italic> gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the <italic>Fmr1</italic> KO rats (<italic>Fmr1<sup>exon4-KO</sup></italic>). 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 <italic>Fmr1<sup>exon4-KO</sup></italic> 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 <italic>Fmr1<sup>exon4-KO</sup></italic> 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 <italic>Fmr1<sup>exon4-KO</sup></italic> rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the <italic>Fmr1</italic> gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the <italic>Fmr1<sup>exon4-KO</sup></italic> rats displayed impaired social interaction and macroorchidism, the results consistent with those observed in patients with FXS. Thus, <italic>Fmr1<sup>exon4-KO</sup></italic> rats constitute a novel rat model of FXS that complements existing mouse models.</p>