The Role of Presynaptic NMDA Receptors in Neocortical Plasticity

Neuroscientists believe that learning and memory are due to changes in connection strength between nerve cells in the brain. In this view, simultaneous activity in connected cells makes their connection grow stronger, and this stores a memory trace of the events in the outside world that evoked the activity. Typically, NMDA receptors detect when connected cells are simultaneously active and they also control how connection strengths are modified. To do this, NMDA receptors need to be positioned on the receiving side of connections between cells, which is exactly what has been found in most brain regions.
My previous research, however, has revealed the existence of NMDA receptors that-although they are clearly involved controlling connection strengths-appear to be situated on the transmitting side of connections. I will figure out the reason for their puzzling location and also clarify how they control connection strengths in the short and long term. In addition, these unorthodox NMDA receptors are found in certain places in the brain. My project will address why this is the case. To summarize, I will investigate how the brain stores information, which may help us understand pathologies due to for example epilepsy or drug use.

It is widely believed that changes in connection strength between neurons underlie learning, memory, and the development of neural circuits. Such synaptic plasticity is brought about by coincident activity in connected neurons. Recently, there has been great interest in the millisecond dependence of synaptic plasticity on the relative timing of pre and postsynaptic spikes, a concept termed Spike-Timing-Dependent Plasticity (STDP).
In the canonical view, synaptic plasticity is triggered by the activation of postsynaptic NMDA receptors, which act as coincidence detectors of pre and postsynaptic activity. Recently, however, I have demonstrated an additional and critical mechanistic role for putatively presynaptic NMDA receptors in STDP. In addition, these presynaptic NMDA receptors regulate high-frequency neurotransmission, thereby controlling short-term synaptic plasticity and information processing in the brain.
The characteristic dual need for depolarization and glutamate binding to open NMDA receptors predicts that NMDA receptors involved in synaptic plasticity should be situated postsynaptically to properly function in coincidence detection. The unorthodox location of presynaptic NMDA receptors is therefore very puzzling and raises several intriguing questions about central synapses in general and about NMDA receptor functioning in particular.
Using a combination of several state of the art approaches, I aim to:
1) Localize and characterize presynaptic NMDA receptors, using 2-photon laser scanning imaging, glutamate uncaging, transgenic mice, and pharmacological manipulations.
2) Clarify their role in short-term plasticity, using paired recordings, computer modelling, fluorescence imaging, transgenic mice, and pharmacological manipulations.
3) Elucidate their role in long-term plasticity, using fluorescence imaging, transgenic mice, pharmacology and glutamate uncaging
4) And to examine their differential, synapse and layer-specific expression, using fluorescence imaging, transgenic mice, electrophysiology, morphological reconstructions, and pharmacology.
In addition to elucidating how the healthy brain functions, develops, and stores memories, these aims will help us understand pathologies due to for example epilepsy or illicit drug use.