The role of extrasynaptic NMDA receptors in synaptic transmission and plasticity

Abstract

Receptors located outside of the synapse are a ubiquitous but poorly understood feature of the nervous system. In this thesis, I investigate the sub-cellular distribution of N-methyl-D-aspartate receptors (NMDARs), a molecule critical for neural function, and explore the role extrasynaptic receptors play in neural communication. I have found that in hippocampal slices, extrasynaptic receptors represent a third of dendritic NMDARs, whose subunit composition is comparable to synaptic NMDARs. Furthermore, contrary to prior reports, these receptors form a stable non-mobile pool. Nonetheless, these receptors regularly participate in neural communication, augmenting synaptic strength in response to repetitive presynaptic activation. To test the effect of extrasynaptic NMDARs on plasticity, I took advantage of the fact that different types of physiologic bursts activate varying amounts of extrasynaptic NMDARs. I therefore incorporated these bursts into stimulation parameters for the induction of plasticity. I also measured the calcium flux that enters the cell during plasticity-induction protocols designed to recruit different amount of extrasynaptic NMDARs. Contrary to predictions based on previous work, I find that extrasynaptic receptors do not prevent LTP. Instead, I find that extrasynaptic NMDARs contribute a crucial component to the calcium signal necessary for the induction of plasticity.