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PNNs regulate the Excitatory\/Inhibitory (E\/I) balance in the brain and are formed at the closure of critical periods of plasticity during development. PNN formation is disrupted in Fragile X Syndrome, which is caused by silencing of the fragile X messenger ribonucleoprotein 1 (<jats:italic>Fmr1<\/jats:italic>) gene and loss of its protein product FMRP. FXS is characterized by impaired synaptic plasticity resulting in neuronal hyperexcitability and E\/I imbalance. Here, we investigate how PNN formation is altered in FXS. PNNs are reduced in <jats:italic>Fmr1<\/jats:italic> KO mouse brain when examined by staining for the lectin <jats:italic>Wisteria floribunda<\/jats:italic> agglutin (WFA) and aggrecan. Examination of PNNs by WFA staining at P14 and P42 in the hippocampus, somatosensory cortex, and retrosplenial cortex shows that they were reduced in these brain regions at P14 but mostly less so at P42 in <jats:italic>Fmr1<\/jats:italic> KO mice. However, some differential FMRP regulation of PNN development in these brain regions persists, perhaps caused by asynchrony in PNN development between brain regions in wild\u2010type animals. During development, aggrecan PNN levels in the brain were reduced in all brain regions in <jats:italic>Fmr1<\/jats:italic> KO mice. <jats:italic>Aggrecan<\/jats:italic> mRNA levels were unchanged at these times, suggesting that FMRP is normally an activator of <jats:italic>aggrecan<\/jats:italic> mRNA translation. This hypothesis is buttressed by the observations that FMRP binds <jats:italic>aggrecan<\/jats:italic> mRNA and that ribosome profiling data show that <jats:italic>aggrecan<\/jats:italic> mRNA is associated with reduced numbers of ribosomes in <jats:italic>Fmr1<\/jats:italic> KO mouse brain, indicating reduced translational efficiency. Moreover, <jats:italic>aggrecan<\/jats:italic> mRNA poly(A) tail length is also reduced in <jats:italic>Fmr1<\/jats:italic> KO mouse brain, suggesting a relationship between polyadenylation and translational control. We propose a model where FMRP modulates PNN formation through translational up\u2010regulation of <jats:italic>aggrecan<\/jats:italic> mRNA polyadenylation and translation.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16048-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16048","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T03:16:18Z","timestamp":1705374978000},"page":"1909-1922","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>FMRP<\/scp> regulation of <i>aggrecan<\/i> mRNA translation controls perineuronal net 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