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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 ( Fmr1 exon4-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  Fmr1 exon4-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  Fmr1 exon4-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  Fmr1 exon4-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  Fmr1 exon4-KO   rats displayed impaired social interaction and macroorchidism, the results consistent with those observed in patients with FXS. Thus,  Fmr1 exon4-KO   rats constitute a novel rat model of FXS that complements existing mouse models.

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