Objective Proper brain functioning requires a balance between inhibitory and excitatory synaptic activity. This balance can be maintained by regulating the number of neurotransmitter receptors in the postsynaptic membrane. A major inhibitory synaptic receptor is the hetero-pentameric GABAA Receptor (GABAAR), which is stabilised in the synapse by the intracellular scaffolding protein gephyrin. Gephyrin, in turn, is recruited to and stabilised at the synapse by the adhesion protein neuroligin-2 (NL2). Regulation of synaptic strength involves lateral diffusion of GABAARs into and out of synapses, endocytic downregulation followed by either degradation or membrane re-insertion, and altering the size of gephyrin clusters. Altered GABAAR trafficking is implicated in neurological and psychiatric disorders, including epilepsy and excitotoxicity in ischemia. The underlying mechanisms, however, remain poorly understood.Ubiquitination is a well-known mechanism that regulates protein trafficking and turnover, however its role in stability and plasticity of the GABAergic synapse remains unclear. Preliminary work from the Kittler lab suggests that: 1) the ubiquitin ligase Unk plays a key role in ubiquitination of the GABAAR; 2) gephyrin can be poly-ubiquitinated and that its proteasomal turnover may be regulated by the de-ubiquitinating enzyme OTUD4; 3) NL2 can be mono-ubiquitinated, potentially directing its trafficking, and that the ubiquitin ligase Nedd4 may regulate this process. Thus ubiquitination may play several key roles in regulating the dynamics of receptor, scaffold, and adhesion molecules at the inhibitory synapse. Using molecular, biochemical, cell biological, and state-of-the-art imaging approaches I aim to study how ubiquitination of GABAARs, NL2 and gephyrin affects GABAAR trafficking, and formation and stability of the inhibitory synapse. This may lead to improved understanding of how ubiquitination regulates neuronal excitability in healthy and pathological conditions. Fields of science medical and health sciencesbasic medicineneurologyepilepsymedical and health sciencesbasic medicineneurologystrokemedical and health sciencesbasic medicineneurologyparkinsonmedical and health sciencesclinical medicinepsychiatryschizophrenianatural sciencesbiological sciencesmolecular biologymolecular neuroscience Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNIVERSITY COLLEGE LONDON Net EU contribution € 183 454,80 Address Gower street WC1E 6BT London United Kingdom See on map Region London Inner London — West Camden and City of London Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
