The trouble with spines in fragile X syndrome: density, maturity and plasticity
Highlights
► Defects in the density, shape and turnover of spines occur in FXS. ► How these lead to circuit dysfunction and cognitive-behavioral symptoms is unknown. ► There are still several controversies regarding the exact spine defects in FXS. ► The real problem may be a defect in activity-dependent spine plasticity/maturation. ► Future research should explore further spine integrity and plasticity in FXS.
Introduction
Fragile X syndrome (FXS) is the most common single-gene cause of autism and mental impairment (Hagerman et al., 2010). In this disorder, transcriptional silencing of the Fmr1 gene causes loss of fragile X mental retardation protein (FMRP), a synaptic RNA-binding protein with regulatory roles in both neuronal growth and plasticity (Bassell and Warren, 2008, De Rubeis and Bagni, 2010). Despite what are often disabling behavioral problems and profound intellectual dysfunction, the brains of individuals with FXS are normal in appearance, at least at the level of routine neuroimaging or gross inspection at autopsy. In fact, only a rather subtle, microscopic neuropathological abnormality has been identified in FXS: abnormal dendritic spines in the brain. In contrast, other developmental brain disorders such as neurofibromatosis or tuberous sclerosis are characterized by gross neuroanatomical defects that are readily apparent to the naked eye, including brain tumors, atrophy, or widespread gliosis, all of which contribute to neuronal dysfunction. Importantly, a similar defect in dendritic spines has been identified in the best-studied animal model of FXS, the Fmr1 knockout (KO) mice (Dutch–Belgian Fragile X Consortium, 1994). These mutant mice have reproducible problems with learning and memory and anxiety-like behaviors that are reminiscent of what is seen in humans with FXS (Penagarikano et al., 2007). This makes FXS an ideal neurodevelopmental disorder in which to study how altered signaling in certain molecular pathways leads to synaptic defects and dysfunctional circuits. Based on the symptoms of affected individuals, including cognitive impairment, sensory integration deficits, learning disability, anxiety, and autistic traits, scientists have focused their studies on three brain regions: the cerebral cortex, the hippocampus, and the amygdala. Here, we review what is known about Fmr1 KO mice and humans with FXS in terms of the density, size and shape, and baseline dynamics of dendritic spines, as well as their role in activity-dependent synaptic plasticity. For a discussion of a different dilemma, whether spine defects are directly caused by loss of FMRP or are an epiphenomenon of circuit dysfunction in FXS, please refer to a related review (Portera-Cailliau, 2011).
Section snippets
Spine density
Spine density is an important aspect of network function. As the number of spines increases, so do the number of neuronal connections and the computational power of the brain (Yuste, 2010). It follows, then, that alterations in the numbers of spines would result in significant network dysfunction. This concept prompted neuroscientists, several decades ago, to begin exploring whether the numbers of spines were altered in neuropsychiatric disorders, including those leading to mental retardation
Spine maturity: size, shape and dynamics
The size and shape of dendritic spines are also critical parameters of neuronal function and connectivity. For instance, large spines are associated with bigger presynaptic terminals, and with larger post-synaptic currents (reviewed by Kasai et al., 2010). Likewise, newly formed spines tend to be smaller and therefore establish weaker synapses (Holtmaat et al., 2006). It follows that changes in spine size and turnover (that is, the rate of appearance and disappearance of spines) will also
Future studies: spine plasticity, synaptic ultrastructure, and molecular pathways
After more than two decades of research into the pathophysiology of fragile X syndrome, we are closer to understanding the molecular pathways regulated by FMRP and the synaptic defects associated with this disorder (Bassell and Warren, 2008). Alterations of dendritic spines, the major recipients of excitatory synapses in the brain, are an important clue to the pathophysiology of FXS. This review underscores the need for additional studies to resolve many outstanding controversies surrounding
Spine pathology: cause or consequence of fragile X syndrome
The neuropathological defect in fragile X syndrome is the overabundance of immature dendritic spines in cortical pyramidal neurons. In addition, a number of defects in synaptic plasticity have been uncovered with electrophysiology in Fmr1 KO mice (Pfeiffer and Huber, 2009). In theory, such dysfunctional circuits could lead to abnormal spines and vice versa, so it is still not clear which problem comes first. A better understanding of this cause-and-effect relationship will require additional
Acknowledgments
This work was supported by FRAXA, the Dana Foundation, the NICHD/NIH (Grant R01HD54453), the NIGMS/NIH (training Grant GM08042), and the Medical Scientist Training Program at the David Geffen School of Medicine at UCLA.
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2022, Brain HemorrhagesCitation Excerpt :FXS is a disorder linked to the FMR1 gene. A large number of immature, thin, and long dendritic spines are observed on cortical pyramidal neurons and neurons in other regions of the brain in individuals with FXS and mice with Fmr1 knockout.54,59 FMRP is essential for synaptic development and other synaptic functions.53