Elisa Corti. FMRP regulation of synapse dynamics


Fragile X syndrome is a neurodevelopmental disorder characterized by intellectual disability, deficits in communication and social interaction, and in some cases seizures. This genetic condition is caused by mutations in the FMR1 gene, which encodes FMRP, a RNA-binding protein. FMRP is involved in shuttling and dendritic localization of mRNAs. This protein has also been described to regulate translation repression and protein synthesis for subsets of neuronal transcripts. mRNA profiling studies identified over a hundred distinct mRNAs that are associated with FMRP, including many synaptic proteins. Additional studies demonstrated that FMRP exerts translational control of synaptic proteins such as PSD95, CaMKII and NMDA receptor subunits, suggesting the importance of this protein in synapse regulation. However, how FMRP regulates synapse dynamics at pre- and post-synaptic levels is poorly understood.

Research Challenge

Given the important role of local protein synthesis both in dendrites and axons, this project aims to investigate the alterations in synapse dynamics in Fmr1 KO neurons, in vitro and in vivo, at presynaptic and postsynaptic levels. These questions will be addressed using different models, including subcellular neuronal fractions, neuronal cell cultures and in vivo imaging, combined with advanced fluorescence microscopy and electrophysiology techniques, among other experimental approaches.

At the Center for Neuroscience and Cell biology (CNC), Carlos Duarte, Ramiro de Almeida and Paulo Pinheiro hold an excellent track record in the study of developing and mature synapses, at pre- and post-synaptic levels. Extensive state of the art facilities for imaging live and fixed neurons, as well as for recording neuronal activity in cultured cells and brain slices, using electrophysiology techniques, are available at both CNC and the University of Coimbra.

Supervision and Secondments

The PhD project will be carried out in the ‘Neurotrophin signaling and Brain (dys)function research group at CNC headed by Carlos Duarte. The ESR will enrol in the Doctoral Programme in Experimental Biology and Biomedicine (PDBEB) coordinated by CNC. The project also features secondments (extended stays) at Lundbeck (Kjartan Herrik) and ICL (Vincenzo De Paola).

Supervisors: Carlos Duarte (cbduarte@ci.uc.pt), Ramiro Almeida, Paulo Pinheiro

Host Location: Center for Neuroscience and Cell biology (CNC), University of Coimbra, Coimbra, Portugal.

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