Role of subunit composition of hippocampal N-Methyl-D-Aspartate (NMDA) receptors in the extinction of contextual fear

• Applicant: Ivana Mesic, Ph.D.
• Subject Area: Biological Psychiatry
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193237260

Fear-motivated learning forms a basis for anxiety disorders such as post-traumatic stress disorders. The knowledge how to treat such human diseases is based upon behavioral studies using Pavlovian fear conditioning. Here, a causal relationship between a neutral/conditioned and a negatively valenced/unconditioned stimulus is established inducing a fear response. Importantly, consecutive presentation of the neutral stimulus alone induces extinction of conditioned fear. However, extinction is not erasure of fear memory but a form of new learning. Learning is driven by detecting a mismatch between expected and experienced events. Hence, if there is a failure to form adequate shock expectations fear extinction is largely affected.One important brain region for fear conditioning and extinction is the hippocampus that is fundamental for processing the contextual aspect and expectation violation. On a molecular level, it was shown that during fear extinction the hippocampal extracellular signal-regulated kinase (ERK) is phosphorylated somatonuclearly. Importantly, in animal models, where adequate shock expectations are not established, the somatonuclear ERK-phosphorylation and fear extinction are prevented. The exact mechanism that triggers differential ERK-phosphorylaion patterns is not known.Phosphorylation of ERK highly depends on the upstream activation of N-Methyl-D-Aspartate (NMDA) receptors. These receptors are one of the major mediators of experience-dependent changes at the synapse underlying learning and memory. Specifically, the NMDA receptor subunit composition largely determines the compartmentalized activation of this signaling pathway. While some insight on this process has been gained by studying NR2 subunits, the role of the NR2 and NR3 subunits is largely unknown. Hence, the hypothesis of this application is that success or failure of contextual fear extinction is determined by the subunit composition of hippocampal NMDA receptors.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Jelena Radulovic