Stimulated Emission Depletion (STED) Microscopy Reveals Nanoscale Defects in the Developmental Trajectory of Dendritic Spine Morphogenesis in a Mouse Model of Fragile X Syndrome

Abstract

Dendritic spines are basic units of neuronal information processing and their structure is closely reflected in their function. Defects in synaptic development are common in neurodevelopmental disorders, making detailed knowledge of age-dependent changes in spine morphology essential for understanding disease mechanisms. However, little is known about the functionally important finemorphological structures, such as spine necks, due to the limited spatial resolution of conventional light microscopy. Using stimulated emission depletion microscopy (STED), we examined spine morphology at the nanoscale during normal development in mice, and tested the hypothesis that it is impaired in a mouse model of fragile X syndrome (FXS). In contrast to common belief, we find that, in normal development, spine heads become smaller, while their necks become wider and shorter, indicating that synapse compartmentalization decreases substantially with age. In the mouse model of FXS, this developmental trajectory is largely intact, with only subtle differences that are dependent on age and brain region. Together, our findings challenge current dogmas of both normal spine development as well as spine dysgenesis in FXS, highlighting the importance of super-resolution imaging approaches for elucidating structure-function relationships of dendritic spines.

mTOR in Brain Physiology and Pathologies

“…97). With the use of stimulated emission depletion microscopy (STED), a normal development of spines with only subtle differences was reported in the Fragile X mouse model (301).…”

Fmr1 KO and Fenobam Treatment Differentially Impact Distinct Synapse Populations of Mouse Neocortex

“…However, to date, few studies have directly quantified excitatory synapse changes in FXS. Moreover, previous studies of dendritic spine density have revealed heterogeneous responses to FMRP loss that are age, cell type, and brain area specific (Cruz-Martín et al, 2012; Galvez and Greenough, 2005; Lauterborn et al, 2013; Nimchinsky et al, 2001; Till et al, 2012; Wijetunge et al, 2014). It is clear, however, that glutamatergic mechanisms that modulate excitatory synapse formation and elimination are affected by FMRP loss (Auerbach et al, 2011; Le Duigou et al, 2011; Gallagher et al, 2004; Huber et al, 2000; Vinueza Veloz et al, 2012; Zhang and Alger, 2010).…”

STED microscopy for nanoscale imaging in living brain slices

“…actin content in living brain slices using YFP as label [34,35]. Recently, STED microscopy was used to reveal nanoscale morphological alterations in dendritic spines in a mouse model of fragile X syndrome (FXS) [36].…”