CPP impairs contextual learning at concentrations below those that block pyramidal neuron NMDARs and LTP in the CA1 region of the hippocampus. (1st January 2022)

• Record Type: Journal Article
• Authors: Laha, Kurt; Zhu, Mengwen; Gemperline, Erin; Rau, Vinuta; Li, Lingjun; Fanselow, Michael S.; Lennertz, Richard; Pearce, Robert A.
• Is Part Of: Neuropharmacology. Volume 202(2022)
• Publication Date: 2022-01-01
• Subjects: NMDA receptors -- Contextual fear conditioning -- CPP -- (R, S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid -- LTP -- Long term potentiation; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2021.108846
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Drugs that block N -methyl-d -aspartate receptors (NMDARs) suppress hippocampus-dependent memory formation; they also block long-term potentiation (LTP), a cellular model of learning and memory. However, the fractional block that is required to achieve these effects is unknown. Here, we measured the dose-dependent suppression of contextual memory in vivo by systemic administration of the competitive antagonist (R, S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP); in parallel, we measured the concentration-dependent block by CPP of NMDAR-mediated synapses and LTP of excitatory synapses in hippocampal brain slices in vitro . We found that the dose of CPP that suppresses contextual memory in vivo (EC50 = 2.3 mg/kg) corresponds to a free concentration of 53 nM. Surprisingly, applying this concentration of CPP to hippocampal brain slices had no effect on the NMDAR component of evoked field excitatory postsynaptic potentials (fEPSPNMDA ), or on LTP. Rather, the IC50 for blocking the fEPSPNMDA was 434 nM, and for blocking LTP was 361 nM – both nearly an order of magnitude higher. We conclude that memory impairment produced by systemically administered CPP is not due primarily to its blockade of NMDARs on hippocampal pyramidal neurons. Rather, systemic CPP suppresses memory formation by actions elsewhere in the memory-encoding circuitry. Graphical abstract: Image 1 Highlights: CPP blocks contextual fear conditioning (CFC) with an ED50 dose of 2.3 mg/kg The ED50 (CFC) dose of CPP corresponds to a free aCSF concentration of 53 nM CPP CPP blocks NMDAR-EPSPs and LTP with ED50 concentrations of 434 nM and 361 nM Implication: CPP acts on non-CA1-pyramidal-neuron NMDARs to block learning