Fragile X syndrome (FXS) is an inherited human mental retardation that arises from expansion of a CGG repeat in the Fmr1 gene, causing loss of the fragile X mental retardation protein (FMRP). It is reported that N-methyl-D-aspartate receptor (NMDAR)-mediated facilitation of long-term potentiation (LTP) and fear memory are impaired in Fmr1 knockout (KO) mice. In this study, biological, pharmacological, and electrophysiological techniques were performed to determine the roles of D-aspartate (D-Asp), a modulator of NMDAR, and its metabolizing enzyme D-aspartate oxidase (DDO) in Fmr1 KO mice. Levels of D-Asp were decreased in the medial prefrontal cortex (mPFC ); however, the levels of its metabolizing enzyme DDO were increased. Electrophysiological recordings indicated that oral drinking of D-Asp recovered LTP induction in mPFC from Fmr1 KO mice. Moreover, chronic oral administration of D-Asp reversed behavioral deficits of cognition and locomotor coordination in Fmr1 KO mice. The therapeutic action of D-Asp was partially through regulating functions of NMDARs and mGluR5/mTOR/4E-BP signaling pathways. In conclusion, supplement of D-Asp may benefit for synaptic plasticity and behaviors in Fmr1 KO mice and offer a potential therapeutic strategy for FXS.
Keywords: D-Aspartate; Fear memory; Fragile X syndrome; Long-term potentiation; mGluR5.
© 2023. The Author(s).