Sleep-Dependent Declarative Memory Consolidation—Unaffected after Blocking NMDA or AMPA Receptors but Enhanced by NMDA Coagonist D-Cycloserine

Abstract

Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors.

Behavioral and cognitive effects of the N-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: Initial findings

“…Moreover, Onur et al (2010) and Kuriyama et al (2011) have recently shown that DCS (250 mg and 100 mg single doses) improve declarative and procedural learning, respectively. Feld et al (2013) demonstrated that DCS (175 mg) can enhance sleepdependent declarative memory consolidation.…”

The gap junction blocker mefloquine impairs sleep-dependent declarative memory consolidation in humans

“…During retrieval participants also encoded numbers (Feld et al, 2013) to assess whether mefloquine affects learning performance. Sixteen three-digit numbers were presented on a computer screen for two seconds (500 ms ISI) in three random blocks.…”

“…Preserved sequential firing during replay, as well as the electrophysiological properties of sharp-wave/ripples, suggests that neuronal plasticity emerging during sleep relies on Hebbian processes such as spike timingdependent plasticity (Sadowski et al, 2016). However, blocking AMPA or NMDA receptormediated synaptic signaling, i.e., the foremost neurochemical processes generating such plasticity, does not compromise the contribution of sleep to declarative memory consolidation (Feld et al, 2013), leaving open the question which neuromolecular mechanisms coordinate sleep-induced plasticity.…”

Overnight memory consolidation facilitates rather than interferes with new learning of similar materials - a study probing NMDA-receptors

“…The relationship between sleep and memory maintenance has received detailed attention in the last 20 years (Diekelmann & Born, 2010;Rasch & Born, 2013) and there is widespread interest in enhancing this beneficial effect of sleep on memory (Feld & Diekelmann, 2015), e.g., by enhancing neuronal oscillations (Marshall, Molle, Hallschmid, & Born, 2004;Ngo, Martinetz, Born, & Molle, 2013) or externally cueing replay (Rasch, Buchel, Gais, & Born, 2007;Rudoy, Voss, Westerberg, & Paller, 2009) i.e., processes that support sleepdependent memory. We recently demonstrated that the N-methyl-D-aspartate (NMDA) receptor co-agonist D-cycloserine powerfully enhances sleep-dependent declarative memory consolidation when administered before sleep (Feld, Lange, Gais, & Born, 2013). It is however completely unclear, how this enhancement affects the subtle balance of encoding and memory maintenance in the brain (Richards & Frankland, 2017).…”

“…These findings pose the intriguing question whether the reduction in memories' susceptibility to retro-active interference during sleep is due to a strengthening of the original trace that would be accompanied by enhanced pro-active interference, i.e., whether new memory traces are harder to establish if they overlap with these stronger old memory traces (Osgood, 1948) The oscillatory properties of sleep that support the consolidation process (Staresina et al, 2015) are ideally suited to drive the strengthening of memory traces via long term potentiation (LTP) (King, Henze, Leinekugel, & Buzsaki, 1999), which occurs mainly at glutamatergic synapses and is mediated by NMDA receptors (Malenka & Bear, 2004;Malenka & Nicoll, 1999). Accordingly, we administered D-cycloserine, a drug that supports NMDA receptor activation by binding to its glycine binding site (Sheinin, Shavit, & Benveniste, 2001), to participants after they learned word-pairs, so that peak plasma concentration occurred during the first half of the sleep phase (Feld et al, 2013). Enhancing NMDA receptor activation benefitted the sleep-dependent consolidation specifically of the word-pairs if given during sleep and thus represents the ideal model to test whether memory traces enhanced by sleep introduce detrimental pro-active interference on new learning.…”