Long-term potentiation and the role of N -methyl- d -aspartate receptors

Abstract

N-methyl-d-aspartate receptors (NMDARs) are known for their role in the induction of long-term potentiation (LTP). Here we start by reviewing the early evidence for their role in LTP at CA1 synapses in the hippocampus. We then discuss more recent evidence that NMDAR dependent synaptic plasticity at these synapses can be separated into mechanistically distinct components. An initial phase of the synaptic potentiation, which is generally termed short-term potentiation (STP), decays in an activity-dependent manner and comprises two components that differ in their kinetics and NMDAR subtype dependence. The faster component involves activation of GluN2A and GluN2B subunits whereas the slower component involves activation of GluN2B and GluN2D subunits. The stable phase of potentiation, commonly referred to as LTP, requires activation of primarily triheteromeric NMDARs containing both GluN2A and GluN2B subunits. In new work, we compare STP with a rebound potentiation (RP) that is induced by NMDA application and conclude that they are different phenomena. We also report that NMDAR dependent long-term depression (NMDAR-LTD) is sensitive to a glycine site NMDAR antagonist. We conclude that NMDARs are not synonymous for either LTP or memory. Whilst important for the induction of LTP at many synapses in the CNS, not all forms of LTP require the activation of NMDARs. Furthermore, NMDARs mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission. It is, therefore, not possible to equate NMDARs with LTP though they are intimately linked.This article is part of a Special Issue entitled SI: Brain and Memory.

Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling

“…The initial large potentiation is termed STP and may itself have various components [1]. Importantly, such STP can be evoked in isolation (without LTP) by much weaker stimulation protocols (even a short burst of action potentials) [2].…”

A Spiking Working Memory Model Based on Hebbian Short-Term Potentiation

“…Once formed, it is also long-lived, which is incompatible with a volatile memory, such as WM. In the past few years, however, different early forms of LTP, such as E-LTP (Park et al, 2014) and STP (Erickson et al, 2010;Volianskis et al, 2015), have been characterized experimentally and proposed as candidates for a synaptic WM. This includes observations that fast STP can last for 6 h when there are no or very few presynaptic (read-out) spikes , suggesting activity-, rather than time-dependent, decay mechanisms for memory.…”

GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets

“…Depending on the nature of the neuron's depolarization, NMDA-Rs can both strengthen synapses, through longterm potentiation (LTP) [32,33], and weaken synapses, through long-term depression (LTD) [34]. For LTP, repetitive and strong depolarization of the neurons allows significant influx of Ca 2+ into the cytoplasm and activation of protein kinases, including the calcium/calmodulindependent protein kinase II (CaMKII), which (a) phosphorylate and activate AMPA-Rs and (b) trigger the insertion of additional AMPA-Rs into the postsynaptic membrane [35].…”