Orsolya Antal. Cognitive disorders as defects in synaptic function: insight from human mutations in the CACNG2 gene encoding Stargazin.
Alterations in neuroplasticity and glutamatergic hypofunction are prominent features of cognitive disorders like intellectual disability (ID) and schizophrenia. One working model for these disorders is based on the disruption of normal homeostatic adaptation of neuronal circuits to changes in the environment, as a consequence of impaired synapse function. The CACNG2 gene encodes the synaptic protein stargazin, an AMPA receptor auxiliary protein for which we have recently uncovered a role in homeostatic synaptic plasticity mechanisms.
The recent finding of ID- and schizophrenia-associated mutations in the stargazin gene prompts the analysis of their functional impact. In this project, we will perform morphological, electrophysiogical and behavioural analyses of knock-in mice expressing disease-associated human variants of stargazin, and image neural circuit dynamics with a voltage-sensitive fluorescent protein. These analyses will allow identifying a neural signature of illness associated with stargazin mutations, and compare shared and distinct defects triggered by stargazin variants associated with ID and schizophrenia. Guided by a specific hypothesis, the potential therapeutic effects of an antidepressant drug using the knock-in models of disease, will be tested.
The group led by Professor Ana Luísa Carvalho at the Center for Neuroscience and Cell biology (CNC), University of Coimbra has long-standing expertise in synapse function and structure, and in particular in AMPA-type glutamate receptors and their auxiliary proteins. Their approaches using cell biology, biochemistry, electrophysiology and behavioral analyses will be complemented by the know-how in imaging cortical dynamics of the secondment institution (ICL). The ESR will also acquire skills in Medical writing, clinical trials development and regulatory affairs at Eurtrials.
Supervision and Secondments
The PhD project will be carried out in the Synapse Biology research group at CNC headed by Ana Luísa Carvalho. 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 ICL (Thomas Knöpfel) and Eurotrials (now CTI; Ana Cláudia Patacão).
Supervisor: Ana Luísa Carvalho (firstname.lastname@example.org)
Host Location: Center for Neuroscience and Cell biology (CNC), University of Coimbra, Coimbra, Portugal.