Unconventional nmdar signaling theory for fragile x syndrome
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID), and the leading known genetic cause of autism. This dominant phenotype represents a huge hindrance for clinicians in the treatment of FXS because the underlying neuronal deficits remain unknown. Individual neurons store information as we learn and acquire new information by modifying their connections with nearby neurons, a process called synaptic plasticity. This refers to activity-dependent long-term changes in synaptic strength but also synaptic structure, and is highly regulated by NMDA receptors (NMDAR). It has recently been proposed that NMDARs can signal in an unconventional manner. Our goal is to understand how unconventional NMDRs drive synaptic plasticity, and how this is dysregulated in the mouse model of FXS. For this, we will record electrical activity of the neurons and image synaptic structures during different forms of synaptic plasticity, and characterise metabotropic NMDAR signaling by functional genomic approaches. 
In summary, we will use a multi-disciplinary approach to unravel the mechanisms responsible for synaptic plasticity alteration in the mouse model for FXS and further our understanding of the neuronal processes underlying cognitive phenotypes of FXS. The outcomes of these experiments will not only offer hope to patients with FXS but will also further our understanding of the molecular basis of synaptic plasticity. If successful, this could serve as the basis for future molecular targets to promote cognitive recovery from ID, autism spectrum disorders and other diseases.
The project is an excellent opportunity for the researcher to further develop her knowledge and to position her in unique multidisciplinary environment that will foster her career progression towards independence. The researcher’s experience acquired at MIT and during the outgoing phase at McGill will be extremely valuable for the host institution and the European research area.