Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome.

Ke Cheng,Yu-Shan Chen,Dan Liu,Gui-Rong Cheng,Lang Xu,Si-Ming Zhang,Yan Zeng,Hong-Xin Dong,Ya-Ping Pei,Chao-Xiong Yue

doi:10.3389/fnins.2019.01098

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability, as well as the leading monogenic cause of autism spectrum disorders (ASD), in which neurons show aberrant dendritic spine structure. The reduction/absence of the functional FMRP protein, coded by the X-linked Fmr1 gene in humans, is responsible for the syndrome. Targets of FMRP, CLSTN1, and ICAM5, play critical roles in the maturation of dendritic spines, synapse formation and synaptic plasticity. However, the implication of CLSTN1 and ICAM5 in dendritic spine abnormalities and the underlying neuropathologic processes in FXS remain uninvestigated. In this study, we demonstrated that CLSTN1 co-localizes and co-transports with ICAM5 in cultured cortical neurons. Also we showed that shRNA-mediated downregulation of CLSTN1 in cultured WT neurons increases ICAM5 on the surface of synaptic membrane, subsequently affecting the maturation of dendritic spines. Whereas, normalization of CLSTN1 level in Fmr1 KO neurons reduces ICAM5 abundance and rescues impaired dendritic spine phenotypes. Most importantly, CLSTN1 protein is reduced in the postnatal medial prefrontal cortex of Fmr1 KO mice, which is correlated with increased ICAM5 levels on the surface of synapses and excessive filopodia-like spines. In conclusion, this study demonstrates that CLSTN1 plays a critical role in dendritic spine formation and maturation in FXS by regulating ICAM5 redistribution.

Highlights

Dendritic spines are small membranous protrusions that constitute the primary postsynaptic sites of excitatory neurotransmission in the brain
intercellular adhesion molecule 5 (ICAM5) is highly expressed in the postnatal Fmr1 Fmr1 knock out (KO) mice, and we can observe the number of immature dendritic spine was higher in Fmr1 knock out (Fmr1 KO) mice started from P14 to P30 (Figure S5). These data suggest the alteration in CLSTN1 and ICAM5 may correlate with the excessive filopodia-like spines in Fmr1 KO mice. Both CLSTN1 and ICAM5 were previously identified by HITSCLIP as fragile X mental retardation protein (FMRP) targets (Darnell et al, 2011), but subsequent analyses of their molecular mechanisms linked to Fragile X syndrome (FXS) or FMRP are lacking
In this study, using both in vivo and in vitro approaches, we demonstrated a key role of CLSTN1 in mediating the intracellular redistribution of ICAM5 within neurons, in which, it subsequently affects the maturation of dendritic spines in the normal brain

Summary

Introduction

Dendritic spines are small membranous protrusions that constitute the primary postsynaptic sites of excitatory neurotransmission in the brain. FXS is a neurodevelopmental disorder that causes intellectual disability and behavioral deficits, it is a leading genetic cause of autism spectrum disorder (ASD), in which the neurons show immature postsynaptic dendritic spine protrusions as thin, actin-rich filopodia on the surface of dendrites (Comery et al, 1997; Cruz-Martin et al, 2010; Wijetunge et al, 2014). The mechanisms underlying dendritic spine abnormalities in FXS are still not well-understood

Methods

Results

Conclusion