| First Author | Cornille M | Year | 2022 |
| Journal | J Exp Med | Volume | 219 |
| Issue | 4 | PubMed ID | 35254402 |
| Mgi Jnum | J:344353 | Mgi Id | MGI:7345439 |
| Doi | 10.1084/jem.20201879 | Citation | Cornille M, et al. (2022) FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model. J Exp Med 219(4):e20201879 |
| abstractText | Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis. |
