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New neurodevelopmental insights that link Fragile X syndrome and autism spectrum disorders.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID), as well as the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by the absence or incorrect production of the protein FMRP (Fragile X Mental Retardation Protein). Scientists at VIB and KU Leuven, in collaboration with Tor Vergata University and VU University of Amsterdam have pinpointed a novel role that FMRP plays during the embryonic development of the brain cortex.

The study reveals that the absence of FMRP leads to a delay in the proper formation of the cortex and shows that FMRP is responsible for transformation of neurons into a locomotion mode to reach their final position in the cortex. This delay in the neurodevelopmental program has an effect on the early postnatal life and the fine-tuning of brain connectivity.

The research underlines the critical role of FMRP in brain development, more specifically in the correct positioning of brain cells during the early stages of development of the cortex. These findings contribute to the current understanding of Fragile X and might provide insights into the cellular mechanisms affected in patients with Fragile X that have autism spectrum disorders and epilepsy, two neurological disorders marked by affected cortical development and brain connectivity.

The study of the Fragile X syndrome (FXS) has been the research object of the team for more than 15 years. Using a mouse model for FXS the researchers proved that FMRP regulates the maturation (multipolar to bipolar) and positioning of the brain cells in the cortex during embryonic development. Furthermore the team unravelled the molecular mechanism through which FMRP regulates these processes and were able, upon the reintegration of FMRP in the embryo, to normalize the early postnatal brain wiring deficits.

The brain cortex is the domain of the brain where information from the rest of the body is received, processed and interpreted. The elaborated information is then converted into thoughts and concrete driving signals for the body. Thus, mistakes or delays in the correct development of the brain cortex are thought to lead to an impaired ability to interpret and process information required for our daily life. Because affected brain connectivity is a hallmark of ASD, this study might explain why some patients with FXS have autism-related symptoms.

The team could demonstrate that in a healthy brain FMRP assures the correct production of the protein N-Cadherin. In the absence of FMRP the levels of N-cadherin are reduced with the consequence that neuronal cells are delayed in their maturation, a developmental program called multipolar to bipolar transition, which is prerequisite for correct positioning in the cortex during development. The team showed that the re-introduction of FMRP or N-cadherin before birth normalised the maturation and positioning of the brain cells and the wiring deficits observed at early postnatal stages.

The scientists then combined the cellular and molecular approaches with high-resolution DTI-MRI (Diffusion-Tensor Imaging – Magnetic Resonance Imaging). Currently, DTI-MRI is one of the most powerful tools to anatomically investigate brain connectivity, as it can be used to study the orientation and integrity of white matter tracts. Taking advantage of an extremely powerful MRI system for small animals, which enables to scan the brains of FXS mice, the scientists obtained structural information of the juvenile FXS mouse brain that revealed abnormalities in the connectivity of the cortex.

The observations, while contributing further to the understanding of the wide spectrum of FXS symptomatology, strengthen the importance of embryonic development for postnatal brain activity and circuitry in FXS and related disorders.

Impaired brain connectivity has been recognized as a candidate key defect in ASD. The future challenge will be to understand how to improve those deficits at very early postnatal stages, for example enriched environmental conditions and also to establish sophisticated MRI strategies with prognostic value for FXS to ultimately guide parental counseling.

Source:  VIB (the Flanders Institute for Biotechnology)

In the brains of normal mice, the six-layered neocortex-indicated by the red marker and shown in the upper right corner-is located adjacent to the three-layered olfactory cortex-indicated by the bright green marker, which also labels layer 5 of the neocortex. If the Lhx2 is missing during a critical period, the neocortex is transformed into olfactory cortex.  Image: Courtesy of Dr. Shen-Ju Chou, Salk Institute for Biological Studies.
In the brains of normal mice, the six-layered neocortex-indicated by the red marker and shown in the upper right corner-is located adjacent to the three-layered olfactory cortex-indicated by the bright green marker, which also labels layer 5 of the neocortex. If the Lhx2 is missing during a critical period, the neocortex is transformed into olfactory cortex. Image: Courtesy of Dr. Shen-Ju Chou, Salk Institute for Biological Studies.

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