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FMRP is an RNA-binding protein that regulates the synthesis of synaptic proteins which are essential for proper brain function. Although circuit hyperexcitability is a hallmark of fragile X syndrome (FXS), the cell-autonomous effects of FMRP deficiency remain poorly understood. In this work, we investigated the functional consequences of the absence of FMRP on neuronal morphology and on ionotropic glutamate receptor surface distribution, using primary cultures of mice hippocampal neurons isolated from wild-type (WT) and <jats:italic>Fmr1<\/jats:italic> knock-out (KO) pups. MAP2 staining of <jats:italic>Fmr1<\/jats:italic> KO neurons showed a decrease in total dendritic length and complexity of the dendritic tree, accompanied by an increase in soma size compared to WT neurons. Moreover, immunolabelling of surface glutamate receptors performed under non-permeabilising conditions showed that <jats:italic>Fmr1<\/jats:italic> KO neurons presented a higher content of synaptic surface GluN2A and a lower content of GluN2B subunits of NMDA receptors, while GluA1 and GluA2 distribution remained unchanged. Finally, multielectrode array data showed that <jats:italic>Fmr1<\/jats:italic> KO neurons presented reduced spontaneous activity compared to control neurons. These data support the hypothesis that at the cellular level, <jats:italic>Fmr1<\/jats:italic> KO hippocampal neurons are less excitable due to altered input processing, driven by structural defects and altered GluN2A expression in the synaptic plasma membrane.<\/jats:p>","DOI":"10.1007\/s12031-025-02325-8","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T06:25:35Z","timestamp":1743747935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["FMRP Controls Neuronal Architecture and Synaptic Content of NMDA Receptors in Cultured Hippocampal Neurons"],"prefix":"10.1007","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7536-6881","authenticated-orcid":false,"given":"Elisa","family":"Corti","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1474-0208","authenticated-orcid":false,"given":"Carlos B.","family":"Duarte","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"2325_CR1","doi-asserted-by":"crossref","unstructured":"Afonso P, De Luca P, Carvalho RS, Cortes L, Pinheiro P, Oliveiros B, Almeida RD, Mele M, Duarte CB (2019) BDNF increases synaptic NMDA receptor abundance by enhancing the local translation of Pyk2 in cultured hippocampal neurons. 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