METAFRAX · Unconventional NMDAR signaling theory for Fragile X Syndrome
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-02-01 → 2025-01-11
- EU contribution
- €244,385
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Unconventional NMDAR signaling theory for Fragile X Syndrome
The METAFRAX project aims at developing the seeds for new pharmacotherapeutic strategies for neurological disorders associated with intellectual disability and autism. Fragile X syndrome is the most common cause of inherited intellectual disability, and the leading known genetic cause of autism. This dominant phenotype represents a huge hindrance for clinicians in the treatment of Fragile X syndrome. Indeed, at present, there are no mechanism-based therapies for intellectual disability and autism. The main obstacle has been to identify the defective cellular processes in the brain that disrupt behavior and cognition. Earlier work on monogenic animal models of Fragile X syndrome supported the idea that one axis of pathophysiology in the syndrome is synaptic plasticity and NMDA receptor-mediated protein synthesis (NMDAR). Moreover, it has recently emerged that NMDAR can signal in a non-conventional manner, but this new mode of operation has yet to be characterized. In this line, the first phase of this METAFRAX project pretended to develop the following key idea: when dysregulated, unconventional NMDAR signaling play a key role in the synaptic physiopathology of intellectual disability and autism associated with Fragile X syndrome. The first objective was to understand how unconventional NMDRs drive synaptic plasticity, by characterizing a new signaling cascade downstream non-ionotropic NMDAR. The second objective was to determine if this is dysregulated in the mouse model of Fragile X syndrome. Overall, this project provides the basis for the future discovery of therapeutic targets for Fragile X syndrome and other cognitively impaired conditions.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
Links
Data: CORDIS, © European Union