Glutamate Receptors and Synaptic Plasticity in Health and Disease: A Personal Journey

I describe my progress in understanding synaptic plasticity in the hippocampus. Over the decades my lab has focused on the roles of glutamate receptors (AMPARs, NMDARs, mGluRs and KARs) and associated signaling molecules in LTP and LTD. Most of our studies have been conducted in area CA1 (Schaffer collateral-commissural pathway) with some conducted in CA3 (mossy fiber pathway). We have made extensive use of electrophysiology and pharmacological tools, complemented with knock-out (KO) and transgenic mice, biochemistry and dynamic imaging. From a starting point in 1980, with essentially no molecular insights available, we have developed a detailed, but still incomplete, mechanism for LTP at CA1 and CA3 synapses as well as providing insights into LTD at CA1 synapses. We have also explored how dysregulated synaptic plasticity contributes to brain disorders, with an emphasis on Alzheimer's disease. Indeed, through a molecular understanding of synaptic plasticity, now we can explain how plaques and tangles are related mechanistically and, in essence, how the early stages of dementia are triggered. Therapeutic strategies, both pharmacological and lifestyle, for tackling dementia are touched upon. Our work, together with that of many other groups, has resulted in massive progress in the understanding of synaptic plasticity in the mammalian CNS in health and disease.