AbstractSleep consolidates declarative memory by the repeated replay of neuronal traces encoded during prior wakefulness. This replay during sleep is linked to the cardinal oscillations of NonREM sleep. Although this replay is ideally suited to support plasticity, there is so far little evidence of classical glutamatergic plasticity playing a role in this process. To the contrary, we have previously reported that blocking NMDA or AMPA receptors does not affect sleep-dependent consolidation of declarative memory. Here, in two placebo-controlled within-subject cross-over experiments with 20 healthy humans each, we used fenobam to block metabotropic glutamate receptor 5 (mGluR5) during sleep. In Experiment I, participants learned word-pairs (declarative task) and a finger sequence (procedural task) during the evening before being administered the treatment and then sleeping for 8 hours – recall was tested in the next morning. To cover possible effects on synaptic renormalization processes during sleep, in Experiment II, participants learned new word-pairs in the morning after sleep. Surprisingly, fenobam neither reduced retention of memory across sleep nor new learning after sleep, although it severely altered sleep architecture and memory-relevant EEG oscillations. In NonREM sleep, fenobam suppressed 12-15 Hz spindles but augmented 2-4 Hz delta waves, whereas in REM sleep it suppressed 4-8 Hz theta and 16-22 Hz beta waves. Notably, under Fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. Our findings indicates that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations.
Discovery of 2-(2-Benzoxazoyl amino)-4-Aryl-5-Cyanopyrimidine as Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptor 5 (mGlu5): From an Artificial Neural Network Virtual Screen to an In Vivo Tool Compound
