Project 458946

Learning and memory are mediated by long-term changes in the strength of connections between neurons, known as synapses. This neuroplasticity occurs in the hippocampal brain region and critically depends on NMDA receptors. Dysfunction of NMDA receptors is central to the development of brain disorders where neuroplasticity is abnormal, such as Alzheimer's disease, schizophrenia, and autism spectrum disorder. NMDA receptors have an essential component, GluN1, which normally has 'a' and 'b' subtypes. The balance between GluN1a and GluN1b was recently found to be disturbed in brain disorders. To understand the importance of these two receptor forms, our lab used genetic tools to generate mice that only have GluN1a- or GluN1b-containing NMDA receptors. We found that the strengthening of synapses, as well as learning and memory were enhanced in mice with GluN1a-NMDA receptors and impaired in mice with GluN1b-NMDA receptors. However, the mechanisms underlying these functional changes have yet to be understood. In my PhD project, I will determine how GluN1a- and GluN1b-NMDA receptors affect the structural changes at synapses in the hippocampus that mediate long-term memory and the NMDA receptor diversity at hippocampal synapses, which has important functional consequences for plasticity processes. I will also examine whether these two receptor forms affect the weakening of synapses, which underlies forgetting. The proposed study will break new ground in understanding the role of NMDA receptor subtypes in learning and memory. Findings from this study will open the future possibility of developing pharmacology to target specific NMDA receptor subtypes as a therapeutic intervention for brain disorders.