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

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.

Genomic signatures of recent convergent transitions to social life in spiders

“…The gene osmotic avoidance abnormal protein 3 ( osm-3 ), which experienced relaxed selection in social spiders, regulates social feeding and aggregation behavior in nematodes (69). The gene calsyntenin-1 ( clstn1 ), which experienced relaxed selection and accelerated evolution in social spiders, regulates synapse formation and synapse plasticity in mice (70), is essential for chemotaxis learning in nematodes (71), and is a candidate for Fragile X syndrome and autism in humans (70, 72). Finally, the genes synaptosomal-associated protein 25kDa ( snap-25 ), synaptobrevin , and syntaxin-1A ( stx1a ) interact to regulate the secretion of neurotransmitters and neuromodulators (73).…”

“…The copyright holder for this preprint this version posted January 28, 2021. ; https://doi.org/10.1101/2021.01.27.428473 doi: bioRxiv preprint experienced relaxed selection and accelerated evolution in social spiders, regulates synapse formation and synapse plasticity in mice (70), is essential for chemotaxis learning in nematodes (71), and is a candidate for Fragile X syndrome and autism in humans (70,72). Finally, the genes synaptosomalassociated protein 25kDa (snap-25), synaptobrevin, and syntaxin-1A (stx1a) interact to regulate the secretion of neurotransmitters and neuromodulators (73).…”

The Fragile X Mental Retardation Protein Regulates Striatal Medium Spiny Neuron Synapse Density and Dendritic Spine Morphology

“…in cultured Fmr1 KO cortical cells identifies involvement of the synaptic adhesion molecule calsyntenin-1 (CLSTN1), an FMRP target mRNA (Darnell et al, 2011), as a potential mechanism for FMRP-mediated spine stabilization (Cheng et al, 2019). Indeed, it may be that a role for FMRP in spine stabilization is at the heart of these different adult morphological observations, manifesting differently depending on regional or cell type environmental conditions, including those that drive FMRP-dependent synapse elimination (Pfeiffer et al, 2010) to a greater or lesser degree.…”

“…Observations in early postnatal hippocampal development (first week) similarly suggest that postsynaptic expression of FMRP promotes synapse function and maturation (Zang et al, 2013 ), and by adulthood, hippocampal, as well as cortical, Fmr1 KO spine deficits generally manifest as excessive numbers of immature spine types (Antar et al, 2006 ; Grossman et al, 2006 ; He and Portera-Cailliau, 2013 ). Work performed in cultured Fmr1 KO cortical cells identifies involvement of the synaptic adhesion molecule calsyntenin-1 (CLSTN1), an FMRP target mRNA (Darnell et al, 2011 ), as a potential mechanism for FMRP-mediated spine stabilization (Cheng et al, 2019 ). Indeed, it may be that a role for FMRP in spine stabilization is at the heart of these different adult morphological observations, manifesting differently depending on regional or cell type environmental conditions, including those that drive FMRP-dependent synapse elimination (Pfeiffer et al, 2010 ) to a greater or lesser degree.…”

mTOR-Dependent Spine Dynamics in Autism

“…Loss of the FMRP protein, that represses translation of other dendritic spine proteins, increases spine density in the medial prefrontal cortex, basal lateral amygdala, and hippocampus compared with wild type (Qin et al, 2011 ) with a greater proportion of thin spines and a lower proportion of mushroom spines (Jawaid et al, 2018 ) as well as hyperexcitability in the somatosensory cortex and exaggerated LTD in the hippocampus (Bhattacharya et al, 2012 ). This could be due to the reduction in a FMRP target calsyntenin-1 in the medial prefrontal cortex which in turn represses the synaptic protein ICAM5; an increase in ICAM5 in the Fmr1 KO decreases spine maturation; overexpression of calysyntenin rescues spine maturation (Cheng et al, 2019 ).…”