Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP

• Published in: Neuropharmacology 2022-11, Vol.218, p.109215-109215, Article 109215
• Main Authors: Zhu, Mengwen, Perkins, Mark G., Lennertz, Richard, Abdulzahir, Alifayaz, Pearce, Robert A.
• Format: Article
• Language: English
• Subjects: (R)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ((R)-CPP); (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP); Animals; Context preexposure facilitation effect (CPFE); Contextual fear memory; Hippocampus; In-vivo calcium imaging; Memory; Mice; N-Methylaspartate - pharmacology; NMDA receptors (NMDARs); Place cell; Place Cells - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Spatial engram
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2022.109215

We recently reported that the competitive NMDAR antagonist (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) does not suppress NMDAR-mediated field EPSPs (fEPSPNMDA) or long-term potentiation (LTP) in vitro at concentrations that block contextual conditioning in vivo. Here we tested one possible explanation for the mismatch – that the hippocampus is relatively resistant to CPP compared to other brain structures engaged in contextual fear conditioning. Using the context pre-exposure facilitation effect (CPFE) paradigm to separate the hippocampal and extra-hippocampal components of contextual learning, we found that the active enantiomer (R)-CPP suppressed the hippocampal component with an IC50 of 3.1 mg/kg, a dose that produces brain concentrations below those required to block fEPSPNMDA or LTP. Moreover, using in-vivo calcium imaging of place cells and spatial engrams to directly assess hippocampal spatial coding, we found that (R)-CPP dose-dependently reduced the development of place cells and interfered with the formation of stable spatial engrams when it was administered prior to exposing mice to a novel context. Both effects occurred at doses that interfered with freezing to context in CPFE experiments. We conclude that (R)-CPP blocks memory formation by interfering with hippocampal function, but that it does so by modulating NMDARs at sites that are not engaged in vitro in the same manner that they are in vivo – perhaps through interneuron circuits that do not contribute to fEPSPs and are not required to elicit LTP using standard induction protocols in vitro, but are essential for successful mnemonic function in vivo. [Display omitted] •CPP dose-dependently suppressed contextual learning with an IC50 of 3.1 mg/kg.•Non-hippocampal circuits were not more sensitive than hippocampus to CPP.•3 mg/kg CPP reduced place cell formation and spatial engram stability.•Hippocampal pyramidal neuron NMDARs are insensitive to amnestic doses of CPP.•Interneuronal NMDARs are possible targets for CPP-induced amnesia in-vivo.