Dendritic spine instability and insensitivity to modulation by sensory experience in a mouse model of fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and is caused by transcriptional inactivation of the X-linked fragile X mental retardation 1 (FMR1) gene. FXS is associated with increased density and abnormal morphology of dendritic spines, the postsynaptic sites of the majority of excitatory synapses. To better understand how lack of the FMR1 gene function affects spine development and plasticity, we examined spine formation and elimination of layer 5 pyramidal neurons in the whisker barrel cortex of Fmr1 KO mice with a transcranial two-photon imaging technique. We found that the rates of spine formation and elimination over days to weeks were significantly higher in both young and adult KO mice compared with littermate controls. The heightened spine turnover in KO mice was due to the existence of a larger pool of "short-lived" new spines in KO mice than in controls. Furthermore, we found that the formation of new spines and the elimination of existing ones were less sensitive to modulation by sensory experience in KO mice. These results indicate that the loss of Fmr1 gene function leads to ongoing overproduction of transient spines in the primary somatosensory cortex. The insensitivity of spine formation and elimination to sensory alterations in Fmr1 KO mice suggest that the developing synaptic circuits may not be properly tuned by sensory stimuli in FXS.autism | imaging | mental retardation | synaptic plasticity | two-photon microscopy F ragile X syndrome (FXS) is the most common form of inherited mental retardation, affecting about 1 in 4,000 males and 1 in 8,000 females (1). Patients who suffer from FXS exhibit various degrees of cognitive, socio-affective, and sensory-motor abnormalities (2). The syndrome is caused by the expansion of a polymorphic CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene located on the X chromosome (3). The fragile X mental retardation protein (FMRP), which is encoded by the FMR1 gene, binds to many mRNAs and is believed to regulate protein translation in various subcellular locations, including dendrites and dendritic spines (4, 5).The Fmr1 KO mice demonstrate many abnormalities found in FXS patients, such as impairments of learning and memory (6-8), social behaviors (9-11), and sensory processing (12, 13), thus providing an excellent model system to study pathogenic mechanisms underlying FXS. Despite these behavioral abnormalities, the gross structure of the brain is largely intact in FXS patients and in the mouse model of the disorder. The most consistent anatomical finding is an abnormal profile of dendritic spines, postsynaptic protrusions that receive the vast majority of excitatory input in the brains of diverse species (14-17).In FXS, the adult dendritic spine phenotype includes increases in spine density and spine length and the number of immaturelooking spines in the various brain regions examined (15,16,18). Similarly, in the visual and somatosensory cortices of adult Fmr1 KO mice, p...

Enhanced synapse remodelling as a common phenotype in mouse models of autism

“…BTBR mice, the inbred strain identified by behavioural screening to mimic the core behavioural deficits of ASD, also showed a similar spine phenotype. In addition to these three ASD mouse models that were analysed in this study, the Fmr1 knockout (KO) mice, a fragile X syndrome and syndromic autistic mouse model, displayed enhanced spine turnover 45,48 , further supporting the idea that an increase in synapse turnover is a common phenotype across diverse ASD mouse models.…”

“…Sensory inputs of the barrel cortex can be modulated by trimming whiskers in a chess-board pattern 44 . In vivo imaging of gephyrin-GFP-( þ ) and ( À ) spines in the barrel cortex over 2 days at postnatal week 3, combined with chess-board whisker trimming, revealed increase in gain of spines receiving inputs from intracortical neurons in wild-type mice 44,45 ( Fig. 7a,b).…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…Studies in Fmr1 KO mice have further revealed that FMRP regulates protein synthesis-dependent axon pruning, dendritic spine elimination, and actin-dependent stabilization of spines. In Fmr1 KO mice, disruption of this regulation leads to abnormal rates of dendritic spine turnover, delayed stabilization of dendritic spines during development, and absence of experience-induced dendritic spine modulation Li et al, 2009;Chen et al, 2010;Cruz-Martin et al, 2010;Pan et al, 2010;Pfeiffer et al, 2010;Scotto-Lomassese et al, 2011).…”

“…Only recently, studies have begun to analyze the function of FMRP for dendritic spine morphology in vivo in living mice (Cruz-Martin et al, 2010;Pan et al, 2010). These analyses revealed that dendritic spines are more transient and show delayed stabilization in Fmr1 KO mice (reviewed in Portera-Cailliau, 2011).…”

O-GlcNAc transferase regulates excitatory synapse maturity

“…Without affecting spine formation, deleting β-adducin, which regulates actin, perturbed the process by which nascent spines establish functional synapses and impaired long-term memory (19). Fragile X syndrome, a common form of mental retardation, exhibits a higher than normal density of spines but more of them exhibit an immature morphology and their turnover is not affected by sensory experience (9,20). Conversely, the protein Telencephalin arrests the maturation of spines and its removal enhances several forms of learning (13,21,22).…”