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.

Keywords: Hippocampus; Long-term depression, LTD; Long-term potentiation, LTP; N-methyl-d-aspartate receptors, NMDARs; N-methyl-d-aspartate, NMDA; Short-term potentiation, STP.

Fig. 1

NMDAR-dependent synaptic plasticity. (A) The specific NMDAR antagonist AP5 (APV) blocks the induction of LTP. (B) Brief application of NMDA induces a transient depression of the FV and fEPSP followed by a RP of the fEPSP. NMDA was applied locally to the dendritic region of CA1 by passing a 50 nA current to a solution of N-methyl-dl-aspartate contained within an electrophoretic pipette. (C) Bath applied NMDA (50 µM, 1 min; applied as a racemate solution) induces LTD. Data replotted from Collingridge et al. (1983a, 1983b).

Fig. 2

NMDAR-mediated Ca²⁺ entry during high frequency stimulation. (A) Schematic of the experimental arrangement. (B) AP5 reduces the synaptic current and eliminates the dendritic Ca²⁺ transient. (C) Ryanodine does not affect the synaptic current but substantially reduces the dendritic Ca²⁺ transient. (D) Ca²⁺ transients in individual dendritic spines. (E) Ca²⁺ transients are localised. All responses are from voltage-clamped CA1 neurons in response to HFS (100, Hz, 1 s). Modified from Alford et al. (1993).

Fig. 3

PTP, STP and LTP. (A) PTP is recorded in the presence of D-AP5 and decays passively (modified from Volianskis and Jensen (2003)). (B) STP decays in an activity-dependent manner. The time-course plots compare the response to TBS with no pause in stimulation or a 1 h pause in stimulation (modified from Volianskis and Jensen (2003)). (C) STP can be stored for at least 6 h (modified from Volianskis and Jensen (2003)). (D) D-AP5 differentially affects STP and LTP. (E) Concentration–response curves for D-AP5 antagonism define two components of STP and one of LTP. Modified from Volianskis et al. (2013a).

Fig. 4

NMDAR subtype-dependence of STP and LTP. (A) AP5 selectively antagonises one component of STP (STP1) and LTP. (B) NVP resembles AP5. (C) Ro selectively antagonises one component of STP (STP2). (D) UBP resembles Ro. Synaptic plasticity was triggered using theta burst stimulation (TBS). Modified from Volianskis et al. (2013a).

Fig. 5

NMDAR subtype-dependence of STP and LTP. Experiments are identical to those presented in Fig. 3 except a 30 min pause in stimulation was introduced shortly after the delivery of TBS. Modified from Volianskis et al. (2013a).

Fig. 6

NMDA induced rebound potentiation (RP). (A) RP is associated with a larger effect on the peak compared to the slope of the fEPSP. (B) STP is associated with a larger effect on the slope compared with the peak of the fEPSP. (C) RP decays passively. (D) STP decays actively. E. NMDA depresses the FV. (F) TBS has no effect on the FV. (Previously unpublished).

Fig. 7

NMDAR-LTD. (A) NMDA-induced LTD increases with the duration of NMDA application and is not associated with changes in the FV after the recovery from transient depression. (B) NMDA-induced LTD is associated with equal changes in fEPSP slope and amplitude. (C). D-AP5 and L-689,560 both block the induction of LFS-LTD. LFS comprised 1 Hz, stimulation for 15 min. (Previously unpublished).

Fig. 8

Various functions of NMDA receptors. (A) Release of glutamate during low frequency synaptic transmission leads to activation of AMPARs (EPSP) and sparse activation of NMDARs, which is insufficient to induce synaptic plasticity. The predominantly AMPAR-mediated EPSPs are shaped by GABAergic interneurons through GABA acting on GABA_A and GABA_B receptors (IPSP) that prevent over-activation of NMDARs (Bliss and Collingridge, 1993). (B) Release of glutamate during high-frequency synaptic transmission leads to activation of NMDARs due to relief of Mg²⁺ block. This happens because of summation of AMPAR-EPSPs, depolarisation that is mediated by build-up of extracellular K⁺ and GABA_B auto-receptor mediated inhibition of GABA release (Bliss and Collingridge, 1993). (C) Activation of NMDARs triggers a variety of different forms of synaptic plasticity. STP is expressed presynaptically, as an increase in P(r). It comprises two components: STP(2) is induced via activation of GluN2B and 2D containing NMDARs (potentially as a triheteromer located on the presynaptic terminal). STP(1) is induced via activation of GluN2A/B receptors. These could be located postsynaptically and signal (together with AMPARs) to the presynaptic terminal via their flux of K⁺ (Collingridge, 1992; Park et al., 2014; Shih et al., 2013). LTP is induced via activation of GluN2A and GluN2B receptors, with a triheteromer being the dominant species. LTD may involve different subtypes of NMDAR, including diheteromeric GluN2B receptors (Liu et al., 2004).