Title: Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP
Legend: (Left) Context Preexposure Facilitation Effect (CPFE) behavioral paradigm used to assess contextual learning (top), and its dose-dependent suppression by the NMDA receptor antagonist (R)-CPP (bottom). (Right) GCaMP6f imaging method used to measure dorsal hippocampal CA1 pyramidal neuron activity in freely exploring mice during an initial exposure and upon re-exposure the following day (top). (R)-CPP dose-dependently blocked the proportion of place cells and rate map (RM) correlation between sessions 1 & 2 (bottom).
Citation: Zhu, M., Perkins, M. G., Lennertz, R., Abdulzahir, A., & Pearce, R. A. (2022). Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP. Neuropharmacology, 218, 109215. https://doi.org/10.1016/j.neuropharm.2022.109215
Abstract: 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.
About the Lab: Research in the Pearce laboratory is focused on the mechanisms by which general anesthetics alter brain function. We are particularly interested in understanding how modulation of GABAA receptors impairs memory – a fundamental endpoint of anesthesia. For our studies we utilize expressed recombinant receptors and hippocampal brain slices to investigate the roles of specific subunit combinations and cell types in the control of learning and memory.
Investigator: Robert A. Pearce, MD, PhD