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The Journal of Neuroscience - April 2014

The Journal of Neuroscience - April 2014

Stimulated emission depletion (STED) microscopy reveals nanoscale defects in the developmental trajectory of dendritic spine morphogenesis in a mouse model of fragile X syndrome

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 fine morphological 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.

The teams of Valentin Nägerl at the Interdisciplinary Institute for Neuroscience (IINS) of the CNRS and the University of Bordeaux and Peter Kind at the Patrick Wild Centre (PWC) of the University of Edinburgh have shed new light onto the mechanisms of brain development and how it might be altered in autism spectrum disorder (ASD) in their recent publication in the Journal of Neuroscience (May 2014 issue). Their findings challenge our current thinking on how synapses develop in the healthy brain and how this process might be derailed during brain disease.

Our brain has about 100 billion neurons that communicate with one another using a complex language, the meaning of which is determined by the timing and number of electrical signals analogous to the tempo and pitch of a piece of music. At the heart of a neuron´s ability to communicate are synapses, specialised junctions for cell-to-cell communication that are important for many higher brain functions, for instance learning and memory. Our genes and life experiences work together and build well-functioning neural circuits, which allow us to sense, feel, think and take actions. Perturbed communication between neurons is a hallmark of neurological and psychiatric illness. Indeed, post-mortem findings from patients with ASD have led neuroscientists to hypothesize that broken synapses are the primary culprit in many forms of ASD, such as Fragile X syndrome (FXS).

Synapses are very small and therefore studying them with traditional methods is prone to errors and misinterpretations. Yet, knowing their exact shape can tell us many things about their functional properties, for instance how strong they are and how well they can communicate with each other. To overcome this technical problem, the scientists used a novel superresolution imaging technique, called STED microscopy, which provides exquisitely detailed images of synapse morphology.
Their novel approach revealed that as synapses become older they change their shape in a way that makes them less isolated, or less egocentric, and that favours more communication or collaboration between many neighbouring synapses. Contrary to widespread expectation, the shape and maturation of synapses is essentially preserved in the brains of mice with the FXS disease, suggesting synapses are under special protection from the mayhem of the disease.

With their sensitive new approach, the researchers will now go on to investigate how very subtle malformations in synapses might influence brain function. The outcome of these studies will advance our understanding of what goes wrong at the level individual neurons and synapses in the brains of people with ASDs so that we can find new and effective ways to help them.

Prof. Peter Kind will join the Nägerl lab for a sabbatical period during June and July 2014. He will give a series of lectures on his research area (developmental neuroscience) during his tenure as a visiting professor at the University of Bordeaux.
Stay tuned!

- The Journal of Neuroscience - April 30, 201434(18):6405–6412

Authors:
Lasani S. Wijetunge, Julie Angibaud, Andreas Frick, Peter C. Kind, and U. Valentin Nägerl

Contact:
Valentin Nägerl, tel. 05 57 57 10 97