Diversity and regulation of GluN1-NMDA receptor subunits in health and disease.

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All thinking, learning and memory processes in the human brain require synaptic communication mediated by the neurotransmitter glutamate and its receptors. Activation of NMDA-subtype receptors mediates long-term molecular mechanisms that are essential for neuronal plasticity and memory. But their excessive activation can lead to neuronal death. The function and pharmacology of different subtypes of glutamate-activated NMDARs is determined by their subunit composition; this tetrameric ion channel requires two GluN1-type subunits, and two GluN2-type subunits. A wealth of information exists on the developmental and disease regulation of GluN2-type subunits (e.g. GluN2A or GluN2B) (reviewed by Paoletti et al 2013) however, little is known of subtype regulation of the GluN1-NMDAR subunits. Alternative splicing of GluN1 into two major types (GluN1-a and GluN1-b) determines functional and pharmacological properties of NMDA receptors. It has recently been shown that the identity of GluN1 subunits in the hippocampus can modulate synaptic plasticity and memory using mice as experimental models. GluN1-a is associated with enhanced plasticity (Sengar et al 2019) and potentially enhanced excitotoxicity. Thus, whether GluN1-a or GluN1-b abundance or synaptic localisation is affected by aging or disease is of great significance, but it is currently unknown. We have recently confirmed that both types of GluN1 are expressed in human brain samples (unpublished). In this project you would use molecular and electrophysiological methods (e.g. qPCR, patch clamp, Western blotting) to test the abundance and regulation of GluN1 in a mouse model of Alzheimer's disease and an in vitro model of stroke. To increase the impact of your findings, you will analyse human brain using frozen samples to study aging and disease regulation of Glu1N isoforms. This analysis of GluN1 subunit regulation in health, aging and disease will contribute to understanding of healthy aging and neurodegeneration and may result in the identification of new drug targets.