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Review
. 2013 Oct 22:251:120-8.
doi: 10.1016/j.neuroscience.2012.03.049. Epub 2012 Apr 20.

The trouble with spines in fragile X syndrome: density, maturity and plasticity

C X He  1 , C Portera-Cailliau
Affiliations
Review

The trouble with spines in fragile X syndrome: density, maturity and plasticity

C X He et al. Neuroscience. .

Abstract

Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder.

Keywords: Div; EM; FMRP; FXS; Fmr1; GFP; KO; L; LTD; LTP; P; WT; days in vitro; electron microscopy; filopodia; fragile X mental retardation protein; fragile X syndrome; green fluorescent protein; knockout; layer; long-term depression; long-term potentiation; mGluR; metabotropic glutamate receptor; postnatal day; synaptic plasticity; two-photon; wild-type.

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Figures

Figure 1
Figure 1. Regional distributions of reported spine defects in the brain of Fmr1 KO mice
Data on dendritic spines in Fmr1 KO mice is displayed on sagittal cuts through the mouse brain (see Table 1). Data from the adult brain, developing brain (≤P20), and in vitro results from dissociated neurons in culture (hippocampus only) are shown in the top, middle and bottom rows, respectively. Colored stripes indicate the existence of published studies reporting different results on either spine density or maturity. The relative thickness of the colored stripes reflects approximately the relative number of studies supporting one finding or another. Studies that used imaging in living neurons (in vivo or in acute/organotypic brain slices) are indicated by arrowheads next to the stripes. Note that results of studies are much more consistent for the spine immaturity phenotype than for the spine density phenotype. Abbreviations: BF: barrel field; OB: olfactory bulb; S1: somatosensory cortex; V1: visual cortex.
Figure 2
Figure 2. Possible mechanisms to explain spine defects in fragile X syndrome
These cartoons depict the various dendritic spine defects that have been reported or proposed in patients with FXS or in Fmr1 KO mice, as well as the theories that may bring about those defects. (a) Spine maturation and plasticity in wild type mice. During early brain development dendrites are studded with headless protrusions called filopodia. These are highly motile and transient protrusions that play a role in early synaptogenesis. In the adult, dendritic spines can be classified morphologically into three main types: thin, stuffy and mushroom. Thin spines tend to be smaller and have shorter lifetimes (days), whereas mushroom spines tend to be the largest and most stable (weeks to months). Spines are plastic structures such that changes in network activity (e.g., sensory inputs, learning new tasks) can modify the size, shape and turnover to influence synaptic strength (e.g., experience-dependent plasticity, LTP). (b) Spine maturation and plasticity in fragile X syndrome. An over-production of spines (or a failure to prune them after development) can lead to a higher spine density as reported in some studies of Fmr1 KO mice. Alternatively, a delayed maturation of dendritic protrusions results in an overabundance of spines with immature morphologies or higher than normal turnover. In addition, spines in FXS may exhibit defects in activity-dependent plasticity. Potential consequences of a higher spine density on the network might include seizures or an exaggerated response to sensory stimuli due to hyperconnectivity. Potential consequences of having immature spines (delayed stabilization and/or immature morphology) might include problems with learning and memory consolidation, due to a reduction in synapse number or to the formation of weaker, short-lasting synapses. Portential consequences of failure of spines to exhibit normal plasticity (e.g., experience-dependent plasticity) would also include problems with learning and memory, as well as sensory integration defects.
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