ICAM5 as a novel target for treating cognitive impairment in fragile X syndrome

Ya Ping Pei, Yue Yi Wang, Dan Liu, Hui Yang Lei, Zhi Hao Yang, Zi Wei Zhang, Man Han, Ke Cheng, Yu Shan Chen, Jin Quan Li, Gui Rong Cheng, Lang Xu, Qing Ming Wu, Shawn M. McClintock, Ying Yang, Yong Zhang, Yan Zeng

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, resulted from the silencing of the Fmr1 gene and the subsequent loss of fragile X mental retardation protein (FMRP). Spine dysgenesis and cognitive impairment have been extensively characterized in FXS; however, the underlying mechanism remains poorly understood. As an important regulator of spine maturation, intercellular adhesion molecule 5 (ICAM5) mRNA may be one of the targets of FMRP and involved in cognitive impairment in FXS. Here we show that in Fmr1 KO male mice, ICAM5 was excessively expressed during the late developmental stage, and its expression was negatively correlated with the expression of FMRP and positively related with the morphological abnormalities of dendritic spines. While in vitro reduction of ICAM5 normalized dendritic spine abnormalities in Fmr1 KO neurons, and in vivo knockdown of ICAM5 in the dentate gyrus rescued the impaired spatial and fear memory and anxiety-like behaviors in Fmr1 KO mice, through both granule cell and mossy cell with a relative rate of 1.32 ± 0.15. Furthermore, biochemical analyses showed direct binding of FMRP with ICAM5 mRNA, to the coding sequence of ICAM5 mRNA. Together, our study suggests that ICAM5 is one of the targets of FMRP and is implicated in the molecular pathogenesis of FXS. ICAM5 could be a therapeutic target for treating cognitive impairment in FXS.

Original languageEnglish (US)
Pages (from-to)1355-1365
Number of pages11
JournalJournal of Neuroscience
Volume40
Issue number6
DOIs
StatePublished - Feb 5 2020

Keywords

  • Cognitive impairment
  • Dendritic spine maturation
  • FMRP/ICAM5 mRNA interaction
  • Fragile X mental retardation protein
  • Fragile X syndrome
  • Intercellular adhesion molecule 5

ASJC Scopus subject areas

  • Neuroscience(all)

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