Abstract
BackgroundNYX-2925 is a novel N-methyl-d-aspartate receptor (NMDAR) modulator that has been shown to facilitate both NMDAR-dependent long-term potentiation (LTP) in vitro and learning and memory in vivo.ObjectiveThe present studies examine the effects of NYX-2925 on NMDAR-dependent auditory LTP (aLTP) in vivo.MethodsNMDAR-dependent aLTP and NMDAR-dependent auditory mismatch negativity (MMN) was measured, as well as changes in resting-state qEEG power.ResultsNYX-2925 (1, 10 mg/kg PO) increased aLTP 1 h after auditory tetanus measured by the post- minus pre-tetanus difference waveform 140–180 ms post tone onset. NYX-2925 (0.1, 1 mg/kg PO) facilitated MMN measured by the difference waveform (i.e., deviant minus standard tones). NYX-2925 (0.1, 1, 10 mg/kg PO) also enhanced resting-state alpha qEEG power. Conversely, the NMDAR glutamate site antagonist CPP (10 mg/kg IP) reduces alpha power and MMN and produces an opposite effect as NYX-2925 on aLTP.ConclusionsTogether, these data suggest that the activation of the NMDAR by NYX-2925 enhances synaptic plasticity in vivo, which may both reduce symptoms of neurological disorders and serve as a biomarker for drug effects. This is the first demonstration of a long-lasting (1-h post-tetanus) effect of NMDAR modulation on synaptic plasticity processes in vivo using a noninvasive technique in freely behaving animals.
Highlights
NMDA receptor (NMDAR) activity is critical for synaptic plasticity
N-methyl-D-aspartate receptor (NMDAR) are required for the induction of some forms of long-term potentiation (LTP), a form of a long-lasting increase in synaptic strength that is a putative substrate for learning and memory (Luscher and Malenka 2012)
LTP at many excitatory synapses in hippocampal and medial prefrontal cortex (MPFC) slices is blocked by the NMDA glutamate receptor antagonist APV, and by NMDAR channel blockers such as MK-801 and ketamine (Bliss and Collingridge 2013; Davis et al 1992)
Summary
NMDARs are required for the induction of some forms of long-term potentiation (LTP), a form of a long-lasting increase in synaptic strength that is a putative substrate for learning and memory (Luscher and Malenka 2012). The induction, but not long-term maintenance, of LTP at many excitatory synapses in hippocampal and medial prefrontal cortex (MPFC) slices is blocked by the NMDA glutamate receptor antagonist APV, and by NMDAR channel blockers such as MK-801 and ketamine (Bliss and Collingridge 2013; Davis et al 1992). In vivo, learning acquisition and long-term memory formation of hippocampus- and MPFC-dependent tasks are blocked by NMDAR antagonists (Burgdorf et al 2011; Davis et al 1992). 2925 is a novel N-methyl-D-aspartate receptor (NMDAR) modulator that has been shown to facilitate both NMDAR-dependent long-term potentiation (LTP) in vitro and learning and memory in vivo
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