ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1667476
This article is part of the Research TopicThe Role of Cellular Subtypes in Striatal ActivityView all 4 articles
Delayed onset of striatal projection neuron hyperexcitability in Fmr1-/y mice
Provisionally accepted
- University of Pittsburgh, Pittsburgh, United States
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Fragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. Although structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout mice (Fmr1-/y), their developmental onset and contribution to early FXS pathophysiology remain unknown. In this study, we examined the postnatal maturation of SPNs in the dorsomedial striatum (DMS) of Fmr1-/y mice, assessing glutamatergic synaptic inputs and intrinsic excitability. During postnatal development, Fmr1 deficient SPNs display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, Fmr1-/y SPNs exhibit pronounced hyperexcitability in both dopamine D1 receptor–expressing SPNs (D1-SPNs) and D2 receptor–expressing SPNs (D2-SPNs), with more pronounced effects in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for behavioral symptoms in FXS, fails to normalize SPN excitability, suggesting limited efficacy in addressing core SPN dysfunction. Together, these findings reveal that DMS SPN hyperexcitability in Fmr1-/y mice emerges after early postnatal development, pointing to a progressive trajectory of striatal abnormalities. These results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address SPN dysfunction.
Keywords: Striatum, striatal projection neuron, neurodevelopment, fragile x, FMR1, Autism Spectrum Disorder
Received: 16 Jul 2025; Accepted: 28 Sep 2025.
Copyright: © 2025 Peixoto, Nelson, Janeček, Matarazzo and Shih. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rui Peixoto, peixotort@upmc.edu
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