A translational EEG-based approach to assess modulation of long-lasting NMDAR-dependent synaptic plasticity

  • Psychopharmacology (Berl). 2019 Dec;236(12):3687-3693. doi: 10.1007/s00213-019-05341-w.
Jeffrey S Burgdorf  1  2 ,  E P Christian  3 ,  L Sørensen  3 ,  P K Stanton  4 ,  K Leaderbrand  3  5 ,  T M Madsen  3 ,  M A Khan  3 ,  R A Kroes  3  5 ,  J R Moskal  3  5
Affiliations
  • 1. Aptinyx Inc., 1801 Maple Ave, Suite 4300, Evanston, IL, 60201, USA. [email protected].
  • 2. Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60201, USA. [email protected].
  • 3. Aptinyx Inc., 1801 Maple Ave, Suite 4300, Evanston, IL, 60201, USA.
  • 4. Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA.
  • 5. Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60201, USA.
PMID: 31392357 DOI: 10.1007/s00213-019-05341-w
Abstract

Background: NYX-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.

Objective: The present studies examine the effects of NYX-2925 on NMDAR-dependent auditory LTP (aLTP) in vivo.

Methods: NMDAR-dependent aLTP and NMDAR-dependent auditory mismatch negativity (MMN) was measured, as well as changes in resting-state qEEG power.

Results: NYX-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.

Conclusions: Together, 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.

Keywords
Auditory-evoked potentials; EEG; LTP; Mismatch negativity; NMDA receptors.
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