The NMDA receptor as a target for cognitive enhancement

Abstract

NMDA receptors (NMDARs) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Fig. 1

Indirect modulation of NMDARs. (A) Schematic representation of some ways in which NMDAR function can be regulated indirectly. Neurotransmitters, and other neuronal regulators, can facilitate NMDAR function by augmenting the “Hebbian depolarization” and by intracellular regulation. NMDARs are important for (B) synaptic transmission (C) the induction of LTP and (D) the induction of LTD. Note that NMDARs contribute considerably to the synaptic response during high frequency synaptic transmission; in this example the NMDAR-EPSP has summated with the AMPAR-EPSPs (shaded yellow) to fire several action potentials (adapted from Herron et al, 1986). LTP is induced by a brief period of high frequency stimulation whilst LTD is induced by a prolonged period of low frequency stimulation. Key: Different types of receptor populations are shown by a colour-coded symbol. Inward current via AMPARs and NMDARs (carried mainly by Na⁺⁾ contributes to the Hebbian depolarization and is shown by a red arrow. Outward current (carried mainly by the movement of K⁺ (GABA_B) out of the cell or Cl^- (GABA_A) into the cell) opposes the Hebbian depolarization and is depicted by a blue arrow. Ca²⁺ entry is shown by the grey arrow and Mg²⁺ by a black circle.

Fig. 2

Potential sites of action of cognitive enhancers at glutamatergic synapses and structures of some compounds that potentiate NMDAR function. The key is the same as in Fig. 1.

Fig. 3

Inappropriate activation of NMDARs inhibits LTP. The panels show data (left panel; replotted from Coan et al, 1989) and schematics during baseline (centre) and a tetanus (right) under four experimental conditions (from top to bottom): in 1 mM Mg²⁺ (grey shading and black circles), following perfusion with Mg²⁺-free medium, and following the addition of either 20 μM or 200 μM D-AP5 in Mg²⁺-free medium (green shading and circles). Calibration bar is 4 mV and 5 min. Optimal conditions for LTP requires minimal activation of NMDARs except during the induction stimulus (time of delivery of the tetanus is indicated by an arrow). By removing Mg²⁺, NMDAR activation in enhanced throughout the recording period and this inhibits the generation of LTP. A low concentration of D-AP5 normalizes the situation by inhibiting spurious NMDAR activation, but is outcompeted by L-glutamate during high frequency stimulation. However, a high concentration of D-AP5 inhibits NMDARs during high frequency stimulation.

Fig. 4

Sites of intracellular modulation of NMDARs. Schematic representation of the distribution of selected posttranslational regulatory sites on the intracellular C-terminal domains of GluN1, GluN2A and GluN2B NMDAR subunits. Serine (S) phosphorylation sites: GluN1-S₈₉₀, GluN1-S₈₉₆, GluN1-S₈₉₇, GluN2B-S₁₃₀₃, GluN2B-S₁₃₂₃, GluN2B-S₁₄₈₀ (Chung et al., 2004; Leonard and Hell, 1997; Liao et al., 2001; Liu et al., 2006; Sanchez-Perez and Felipo, 2005; Sanz-Clemente et al., 2010; Scott et al., 2001, 2003; Tingley et al., 1997). Tyrosine (Y) phosphorylation sites: GluN1-Y₈₃₇, GluN2A-Y₈₄₂ GluN2A-Y₁₃₃₆, GluN2A-Y₁₃₈₇, GluN2B-Y₁₃₃₆, GluN2B-Y₁₄₇₂ (Lau and Huganir, 1995; Moon et al., 1994; Nakazawa et al., 2001; Vissel et al., 2001; Yang and Leonard, 2001). Cysteine (C) palmitoylation sites: GluN2A-C₈₄₈, GluN2A-C₈₅₃, GluN2A-C₈₇₀, GluN2A-C₁₂₁₄, GluN2A-C₁₂₁₇, GluN2A-C₁₂₃₆, GluN2A-C₁₂₃₉, GluN2B-C₈₄₉, GluN2B-C₈₅₄, GluN2B-C₈₇₁, GluN2B-C₁₂₁₅, GluN2B-C₁₂₁₈, GluN2B-C₁₂₄₂, GluN2B-C₁₂₃₉, GluN2B-C₁₂₄₅ (Hayashi et al., 2009). Calpain cleavage sites: GluN2A-1279, GluN2A-1330, GluN2B∼1030 (approximately) (Dong et al., 2006; Guttmann et al., 2001; Simpkins et al., 2003; Doshi and Lynch, 2009). See text for further details (3.6. Intracellular modulation of NMDARs).

Fig. 5

UBP714 potentiates NMDAR responses A. Data (n = 4, mean ± S.E.M.), showing that UBP714 potentiates NMDAR-mediated GluN1/GluN2A (17 ± 2%, 2A), GluN1/GluN2B (14 ± 1%, 2B) and GluN1/GluN2D (4 ± 1%, 2D) responses in Xenopus laevis oocytes (reprinted from Irvine et al, 2012). The trace to the right shows that 100 μM UBP714 (gray bar) potentiates GluN1/GluN2A NMDAR response, which was evoked by applying 10 μM glutamate and 10 μM glycine (black bar). B. Data (n =10) showing that UBP714 potentiates pharmacologically isolated NMDAR-mediated f-EPSPs (inset) in hippocampal slices from adult rat (19 ± 2%, 1-h after the start of application of 100 μM UBP714, reprinted from Irvine et al, 2012).