FMRP Regulates NrCAM Expression via β-catenin and Modulates PSD95, Dendritic Spines and Autism-like Behaviors

Fragile X mental retardation protein (FMRP) and β-catenin play essential roles in dendritic development and neurobehavior, whereas the neuronal cell adhesion molecule (NrCAM) is closely involved in synapse formation and remodeling. However, whether FMRP regulates NrCAM through β-catenin to influence hippocampal dendritic development and neurobehavior remains unclear. Here, transcriptomic analysis of Fmr1 knockout (KO) mice identified Ctnnb1 as a key differentially expressed gene associated with aberrant dendritic development. FMRP directly binds to β-catenin mRNA in HT22 cells. Fmr1 knockdown upregulated β-catenin, NrCAM, and PSD95 expression at both the mRNA and protein levels and promoted the nuclear accumulation of β-catenin. NrCAM was required for the FMRP deficiency-induced upregulation of PSD95, and simultaneous knockdown of Fmr1 and Nrcam reduced PSD95 expression. Furthermore, Fmr1 knockdown enhanced the interaction between NrCAM and PSD95. In vivo hippocampal Nrcam knockdown in Fmr1 KO mice decreased PSD95 expression, whereas Ctnnb1 knockdown rescued dendritic spine abnormalities and ameliorated autism-like behaviors. These findings demonstrate that FMRP regulates NrCAM through β-catenin to modulate PSD95 expression, thereby influencing hippocampal dendritic spine development and autism-like behaviors. This study provides new mechanistic insights into the neuropathology of hereditary mental retardation.