Long-term potentiation in the hippocampus: From magnesium to memory

Long-term potentiation (LTP) is a widely studied phenomenon since the underlying molecular mechanisms are widely believed to be critical for learning and memory and their dysregulation has been implicated in many brain disorders affecting cognitive functions. Central to the induction of LTP, in most pathways that have been studied in the mammalian CNS, is the N-methyl-D-aspartate receptor (NMDAR). Philippe Ascher discovered that the NMDAR is subject to a rapid, highly voltage-dependent block by Mg²⁺. Here I describe how my own work on NMDARs has been so profoundly influenced by this seminal discovery. This personal reflection describes how the voltage-dependent Mg²⁺ block of NMDARs was a crucial component of the understanding of the molecular mechanisms responsible for the induction of LTP. It explains how this unusual molecular mechanism underlies the Hebbian nature of synaptic plasticity and the hallmark features of NMDAR-LTP (input specificity, cooperativity and associativity). Then the role of the Mg²⁺ block of NMDARs is discussed in the context of memory and dementia. In particular, the idea that alterations in the voltage-dependent block of the NMDAR is a component of cognitive decline during normal ageing and neurodegenerative disorders, such as Alzheimer's disease, is discussed.