Final Activity Report Summary - GLUREHIPLA (Physiological basis of learning and memory processes in the brain) This project concerned synaptic plasticity in relation to learning and memory. This area of research is important both for human health and basic biomedical research. Memory is essential for human identity and our ability to function socially. Its loss is amongst the most devastating aspects of brain disorders such as epilepsy, stroke and Alzheimer's disease. A better understanding of normal memory may lead to better treatment of memory disorders. However, we still do not understand how the dynamics of neuronal activity in the brain gives rise to the lasting traces of experience that underlies memory. Spike timing-dependent synaptic plasticity (STDP) is a strong candidate mechanism, obeying the theoretical predictions made by Donald Hebb and sharing mechanisms with long-term potentiation (LTP) induced by high frequency trains of afferent stimulation as well as long-term depression (LTD) induced by low-frequency synaptic stimulation. Long-term potentiation of synaptic transmission was first described in 1973. The importance of NMDA receptors for induction of LTP as well as spatial memory was established in the 1980s. The identification of multiple types of NMDA receptor subunits and the increasing awareness that NMDA receptor activation can lead to both increase and decrease of synaptic weights have further refined our understanding since these initial discoveries. However, we still do not understand the precise mechanism whereby activation of NMDA receptors can be responsible for opposite changes in synaptic weights. Recently, to identify the location of NMDA receptors necessary for induction of spike timing-dependent potentiation and depression, we used intracellular loading of an NMDA receptor blocker (MK-801) during recordings between pairs of synaptically-connected neurons in barrel cortex. We found that, whereas postsynaptic loading of MK-801 blocked induction of spike timing-dependent potentiation, presynaptic MK-801 did not. In contrast, presynaptic loading of MK-801 blocked the induction of spike timing-dependent depression, whereas postsynaptic loading did not. Thus, postsynaptic NMDA receptors are necessary for LTP, whereas presynaptic NMDA receptors appear to be necessary for LTD. This experimental double dissociation supports a model in which induction of LTP requires postsynaptic NMDA receptors, whereas LTD requires presynaptic NMDA receptors. The different sites of NMDA receptors necessary for LTP and LTD may have important consequences for the computational operation of cortical microcircuits and map plasticity. This result will be published in the journal Nature Neuroscience.