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Review
. 2018 Jul;596(14):2773-2782.
doi: 10.1113/JP275571. Epub 2018 Feb 25.

Imbalance of synaptic actin dynamics as a key to fragile X syndrome?

Kristin Michaelsen-Preusse  1 , Jonas Feuge  1 , Martin Korte  1   2
Affiliations
Review

Imbalance of synaptic actin dynamics as a key to fragile X syndrome?

Kristin Michaelsen-Preusse et al. J Physiol. 2018 Jul.

Abstract

Our experiences and memories define who we are, and evidence has accumulated that memory formation is dependent on functional and structural adaptations of synaptic structures in our brain. Especially dendritic spines, the postsynaptic compartments of synapses show a strong structure-to-function relationship and a high degree of structural plasticity. Although the molecular mechanisms are not completely understood, it is known that these modifications are highly dependent on the actin cytoskeleton, the major cytoskeletal component of the spine. Given the crucial involvement of actin in these mechanisms, dysregulations of spine actin dynamics (reflected by alterations in dendritic spine morphology) can be found in a variety of neurological disorders ranging from schizophrenia to several forms of autism spectrum disorders such as fragile X syndrome (FXS). FXS is caused by a single mutation leading to an inactivation of the X-linked fragile X mental retardation 1 gene and loss of its gene product, the RNA-binding protein fragile X mental retardation protein 1 (FMRP), which normally can be found both pre- and postsynaptically. FMRP is involved in mRNA transport as well as regulation of local translation at the synapse, and although hundreds of FMRP-target mRNAs could be identified only a very few interactions between FMRP and actin-regulating proteins have been reported and validated. In this review we give an overview of recent work by our lab and others providing evidence that dysregulated actin dynamics might indeed be at the very base of a deeper understanding of neurological disorders ranging from cognitive impairment to the autism spectrum.

Keywords: ASD; FMRP; FXS; actin; hippocampus; spines; structural plasticity.

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Figures

Figure 1
Figure 1. Two opposite synaptic phenotypes shown on a single FXS CA3 neuron
In comparison to WT CA3 neurons (left side), FXS neurons (right side) show a hyperabundance of long and thin dendritic spines in the stratum radiatum (right upper tile). Given the fact that FMRP has an important function in mRNA transport and the regulation of local translation, our work suggests that this phenotype might be based on altered actin dynamics, caused by a dysregulation of actin‐binding proteins (ABPs) (right upper tile, here shown for the ABPs profilin 1 (PFN1) and cofilin 1 (CFL)). Surprisingly, we found mossy fibre synapses on CA3 neurons in the stratum lucidum (lower tiles) to be structurally altered as well, having increased numbers of thorny excrescences (TE), containing more surface AMPA receptors as well as more clusters of the ABP synaptopodin.
See this image and copyright information in PMC

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