Project description
New molecular players in brain development
SYNGAP1-related intellectual disability (SRID) is a severe neurodevelopmental disorder characterised by epilepsy, developmental delay, and autism. The SynGAP protein is abundant at excitatory synapses, where it regulates neuronal communication and plasticity. SynGAP may also influence early brain development, guiding cortical cell type specification. With the support of the Marie Skłodowska-Curie Actions programme, the SYNGAP-IsoDev project aims to investigate how different SynGAP isoforms shape neurodevelopmental processes. Researchers will study isoform regulation and function at prenatal and postnatal stages in mouse models and human organoids. Project findings will help identify SynGAP-related disease mechanisms and pave the way for novel therapies for SRID.
Objective
Synaptic Ras GTPase activating protein (SynGAP) is crucial for neuronal communication and is highly concentrated in excitatory synapses. Mutations in the SYNGAP1 gene cause SYNGAP1-related intellectual disability (SRID), a neurodevelopmental disorder characterized by epilepsy, developmental delay, and autism. As there is no cure for SRID, this proposal will elucidate SYNGAP1 expression and function during development. In the adult brain, SynGAP regulates synaptic plasticity by interacting with other proteins to modulate synaptic strength. Recent studies suggest non-synaptic functions for SynGAP during neurodevelopment, regulating cell type specification in early cortical formation. This study will pioneer the investigation of SYNGAP1 isoform function and regulation across brain development.
SYNGAP1 encodes for multiple N- and C-terminal isoforms with unique roles in synaptic function. Mouse models revealed that SynGAP-α1 affects synaptic plasticity, while SynGAP-β influences dendritic growth. Despite this, the regulation of the gene and its mRNA and isoform expression, especially during neurodevelopment, remains poorly understood. Preliminary analysis shows differential SYNGAP1 N-terminal isoform expression prenatally compared to adult brain.
We hypothesize that (i) SYNGAP1 isoform expression is transcriptionally regulated in neurodevelopment with differential isoform usage between pre- and postnatal stages, and (ii) these isoforms have unique functions. We find that CRISPR activation (CRISPRa) upregulates Syngap1 in adult mouse hippocampus, offering a promising approach for modulating isoform expression. To test these hypotheses, we aim to employ cutting-edge techniques in mouse and human SRID models. Approaches include targeted long-read sequencing, intrahippocampal CRISPRa, behavioral phenotyping, and human cortical organoids. The goal is to uncover mechanisms of isoform-specific functions and their impact on SRID, potentially informing new therapies.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine neurology epilepsy
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2024-PF-01
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WC2R 2LS London
United Kingdom
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