Co-agonist Regulation of Pre and Postsynaptic NMDA Receptors in the Entorhinal Cortex

Abstract

The NMDA receptor is a highly diverse receptor with many functions. In particular NMDA receptors present on postsynaptic spines mediate the effects of the synaptic neurotransmitter glutamate, whilst NMDA receptors present on presynaptic nerve terminals directly regulate the release of neurotransmitters. The aim of this thesis was to expand the characterisation of these two populations of NMDA receptors by examining the functional role of the co-agonist binding sites. NMDA receptors have been strongly implicated in mechanisms of cognition and also the pathophysiology epilepsy and so I have focused my study in the entorhinal cortex which is an area increasingly seen to be central to both of these phenomenon. Initial work focussed on the endogenous regulation of the presynaptic NMDA receptors. My results indicated that the co-agonist site of these receptors was activated by D-serine and that this ligand may come from astrocytes, in contrast to the observations that others have made for postsynaptic NMDA receptors. Following this, I then characterised the effects of partial agonists of the NMDA receptor co-agonist site at each of these populations of NMDA receptors and report differential effects for the function of these receptors. Finally I then examined the effects of the co-agonist site ligands on epileptiform activity as a simple form of emergent neuronal network activity. Results from my study of co-agonist site ligands provide important new insights into the relationship between NMDA receptors and neuronal synchrony and also the mechanism of cognitive enhancement by the high efficacy partial co-agonist D-Cycloserine.

Date of Award	25 Sept 2015
Original language	English
Awarding Institution	University of Bath
Supervisor	Roland Jones (Supervisor)