Objective The pathophysiological mechanisms causing schizophrenia are not well known. Schizophrenia is characterized by symptoms such as hallucinations, emotional isolation and cognitive deficits. Altered neurotransmission through the glutamate transmitter system has been linked to this devastating psychiatric illness. In particular, observations that functional antagonism of the N-methyl-D-apartate (NMDA) glutamate receptor by phencyclidine (PCP) worsens all symptoms in patients and induces a schizophrenia-like psychosis in healthy volunteers have implicated this receptor in schizophrenia. The NMDA receptor, which is principally expressed in postsynaptic spines, is a multimeric protein assembly consisting of the obligatory NR1 subunit in different constellations with NR2A or NR2B subunits. Through alternative splicing of NR1, several regulatory domains are introduced in the receptor, which significantly influence early processing including assembly and forward trafficking. Based on functional divergence, receptors assembled from NR2A and NR2B proteins similarly contribute with functional specialization of the receptor. Studies in postmortem brain indicate that mechanisms associated with early NMDA receptor processing might be altered in schizophrenia. This includes evidence for altered NR1 splicing and compromised trafficking of NR2B-type NMDA receptors. Based on a hypothesis of altered NMDA receptor processing, in this project we will use an animal model to study, in a translational manner, changes in alternative splicing, assembly and trafficking of new NR2A and NR2B receptors in schizophrenia. Furthermore, we will analyze if NMDA receptor processing is modulated by peptides known to enhance cognition. Due to the specialized roles NR2A and NR2B receptors play during complex functions such as cognition, improved understanding of how this receptor system is altered in schizophrenia might lead to improved treatment of symptoms not well treated today. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicinepsychiatryschizophrenia Keywords Neurobiology alternative splicing cognition glutamate neurotransmission postsynaptic density protein interaction protein synthesis receptor assembly Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) PEOPLE-2007-4-3.IRG - Marie Curie Action: "International Reintegration Grants" Call for proposal FP7-PEOPLE-IRG-2008 See other projects for this call Funding Scheme MC-IRG - International Re-integration Grants (IRG) Coordinator KOBENHAVNS UNIVERSITET Address Norregade 10 1165 Kobenhavn Denmark See on map Region Danmark Hovedstaden Byen København Activity type Higher or Secondary Education Establishments Administrative Contact Ivan Kristoffersen (Mr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 100 000,00
