CPP impairs contextual learning at concentrations below those that block pyramidal neuron NMDARs and LTP in the CA1 region of the hippocampus

Laha, Kurt T.; Zhu, Mengwen; Gemperline, Erin; Rau, Vinuta; Fanselow, Michael S.; Lennertz, Richard; Pearce, Robert A.

doi:10.1016/j.neuropharm.2021.108846

Cited by 8 publications

(12 citation statements)

References 82 publications

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“…Unlike in vitro intracellular electrophysiology recording, it may be more truly and completely reflect the efficacy of drugs, through some important indicators such as I/O function, PPF ratio and LTP [ 27 , 28 ]. Two major pathways into and out of the hippocampus (the PP-DG pathway and the SCh-CA1 pathway), coordinately maintain synaptic transmission in hippocampus and are suitable to verify the possible effect of synaptic plasticity in the process of fullerenol against lead-induced injury [ 29 – 31 ]. Our results show that fullerenol has the positive impacts on hippocampal plasticity, and can eliminate the inhibitory effect of lead.…”

Section: Discussionmentioning

confidence: 99%

Long-term maintenance of synaptic plasticity by Fullerenol Ameliorates lead-induced-impaired learning and memory in vivo

et al. 2022

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Fullerenol, a functional and water-soluble fullerene derivative, plays an important role in antioxidant, antitumor and antivirus, implying its enormous potential in biomedical applications. However, the in vivo performance of fullerenol remains largely unclear. We aimed to investigate the effect of fullerenol (i.p., 5 mg/kg) on the impaired hippocampus in a rat model of lead exposure. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF–MS) is a kind of newly developed soft-ionization mass spectrometry technology. In the present study, an innovative strategy for biological distribution analysis using MALDI-TOF–MS confirmed that fullerenol could across the blood–brain barrier and accumulate in the brain. Results from behavioral tests showed that a low dose of fullerenol could improve the impaired learning and memory induced by lead. Furthermore, electrophysiology examinations indicated that this potential repair effect of fullerenol was mainly due to the long-term changes in hippocampal synaptic plasticity, with enhancement lasting for more than 2–3 h. In addition, morphological observations and biochemistry analyses manifested that the long-term change in synaptic efficacy was accompanied by some structural alteration in synaptic connection. Our study demonstrates the therapeutic feature of fullerenol will be beneficial to the discovery and development as a new drug and lays a solid foundation for further biomedical applications of nanomedicines.

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Section: Discussionmentioning

confidence: 99%

Long-term maintenance of synaptic plasticity by Fullerenol Ameliorates lead-induced-impaired learning and memory in vivo

et al. 2022

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“…Pharmacological suppression of hippocampal learning and memory through NMDAR antagonists has presumably been related to the suppression of LTP. However, our previous study demonstrated that there is a substantial mismatch in concentrations that block of NMDAR-dependent LTP in vitro and suppression of hippocampus-dependent contextual memory (Laha et al, 2022). Here, using CPFE, and supported by calcium imaging experiments, we established that the IC50 for (R)-CPP is 3.1 mg/kg (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Studies using NMDAR antagonists in particular have revealed a wealth of information about how the molecular composition, spatial and temporal expression patterns, gating kinetics, and pharmacological sensitivities of various NMDAR subtypes influence their physiological roles (Feng et al, 2005; Hansen et al, 2014; Hansen et al, 2018; Lind et al, 2017; Paoletti et al, 2013; Stroebel et al, 2018; Wyllie et al, 2013; Zhu and Paoletti, 2015). One such antagonist, (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), has been widely used for decades, primarily because it readily crosses the blood-brain barrier so it can be administered systemically, but also because it is water soluble, making it convenient to use both in vitro and in vivo (Bergeron and Rompre, 2013; Fung et al, 2016; Gemperline et al, 2014; Harris et al, 1986; Hayashi, 2019; Laha et al, 2022; Lehmann et al, 1987; Wang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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

Zhu¹,

Perkins²,

Lennertz³

et al. 2022

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A common way to study the functional importance of N-methyl-D-aspartate receptors (NMDARs) in hippocampal memory-encoding circuits is by administering NMDAR antagonists. We recently compared the effects of (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive NMDAR antagonist, on suppression of memory in vivo versus suppression of NMDAR-mediated field EPSPs (fEPSPNMDA) and long-term potentiation (LTP) in vitro. Surprisingly, we found that concentrations that block contextual conditioning in vivo are ineffective at blocking the fEPSPNMDA or LTP in vitro. 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. We used the context pre-exposure facilitation effect (CPFE) paradigm to isolate the hippocampal component of contextual learning, and in-vivo calcium imaging of place cells and spatial engrams to directly assess hippocampal spatial coding. We found that, by both measures, the active enantiomer (R)-CPP did interfere with hippocampal function at concentrations below those that block fEPSPs or LTP. We conclude that the alternative—that CPP interferes with memory by targeting NMDARs in interneurons rather than pyramidal neurons—is the more likely explanation.

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“…In contrast, CPP decreased theta peak rise and theta‐γ CFC similarly in KO and WT mice (Tables 5, 6), and decreased beta and γ waves more in KO than WT mice. The decrease in theta power or theta‐γ CFC, and increase in delta power or delta‐γ CFC, during walk could explain the dyscognitive effects of both scopolamine (Givens & Olton, 1990; Rogers & Kesner, 2003) and CPP (Laha et al, 2022; Upchurch & Wehner, 1990). The present dose of 10 mg/kg i.p.…”

Section: Discussionmentioning

confidence: 99%

“…CPP at 3 and 5 mg/kg i.p. were effective to suppress contextual learning (Laha et al, 2022) and spatial learning (Upchurch & Wehner, 1990), respectively. Recordings were made at 10–55 min after injection of scopolamine, and at 30–90 min after injection of CPP.…”

Section: Methodsmentioning

confidence: 99%

Muscarinic and N‐methyl‐D‐aspartate receptor blockade reveal differences in hippocampal local field potentials in mice with low cholinergic tone

et al. 2022

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We hypothesize that hippocampal local field potentials in acetylcholine (ACh)‐deficient mutant mice, compared to wild‐type (WT) mice, will show lower sensitivity to muscarinic cholinergic antagonist scopolamine (5 mg/kg i.p.) but higher sensitivity to NMDA receptor antagonist 3‐(2‐carboxypiperazin‐4‐yl)propyl‐1‐phosphonic acid (CPP, 10 mg/kg i.p.). Recordings were made during walk and awake‐immobility (IMM) in WT mice, and in mice with forebrain knockout (KO) of the vesicular acetylcholine transporter (VAChT) gene, or heterozygous knockdown of VAChT gene (KD). Scopolamine or CPP did not significantly alter walk theta frequency, which was higher in KD than WT/KO mice. Scopolamine decreased theta power peak rise during walk in WT/KD mice but not in KO mice, while CPP suppressed theta peak rise more in WT/KO mice than KD mice. During IMM, scopolamine decreased gamma1 (γ1, 30–58 Hz) power more in KD/WT mice than KO mice, while delta (1–4 Hz) power and delta‐gamma cross‐frequency coherence (CFC) were increased in all mouse groups during IMM or walk. During walk, scopolamine increased delta and beta (13–30 Hz) power and decreased gamma2 (γ2, 62–100 Hz) power and theta‐γ2 CFC more in WT/KD than KO mice. Theta‐γ2, but not theta‐γ1, CFC increased with theta‐peak‐frequency in WT/KD mice, and was suppressed by scopolamine at high theta (8–10 Hz) frequency; theta‐γ2 CFC in KO mice was not significantly altered by scopolamine. CPP decreased beta and gamma power more in KD/KO mice compared to WT mice, while delta power and delta‐gamma CFC were increased in all mouse groups. ACh deficiency exacerbates the attenuation of beta and gamma power by CPP. We conclude that both muscarinic and NMDA transmission contribute toward hippocampal theta, beta, and gamma power, and a decrease in gamma power or theta‐gamma CFC may be associated with loss of arousal and cognitive functions.

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CPP impairs contextual learning at concentrations below those that block pyramidal neuron NMDARs and LTP in the CA1 region of the hippocampus

Cited by 8 publications

References 82 publications

Long-term maintenance of synaptic plasticity by Fullerenol Ameliorates lead-induced-impaired learning and memory in vivo

Long-term maintenance of synaptic plasticity by Fullerenol Ameliorates lead-induced-impaired learning and memory in vivo

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

Muscarinic and N‐methyl‐D‐aspartate receptor blockade reveal differences in hippocampal local field potentials in mice with low cholinergic tone

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