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Differential Effects of D-Cycloserine and ACBC at NMDA Receptors in the Rat Entorhinal Cortex Are Related to Efficacy at the Co-Agonist Binding Site.

Lench AM, Robson E, Jones RS - PLoS ONE (2015)

Bottom Line: In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses.Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid.We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.

ABSTRACT
Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

No MeSH data available.


Related in: MedlinePlus

ACBC reduces preNMDAr activity.A. The histogram shows normalised frequency data for 5 neurones and indicates a significant decrease in frequency in the presence of the low-efficacy partial agonist. B. There was no concurrent change in frequency distribution of event amplitudes. C. The averaged mEPSCs recorded in one neurone illustrate that peak amplitude, rise and decay times of events was unaltered by ACBC. * P<0.05
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pone.0133548.g007: ACBC reduces preNMDAr activity.A. The histogram shows normalised frequency data for 5 neurones and indicates a significant decrease in frequency in the presence of the low-efficacy partial agonist. B. There was no concurrent change in frequency distribution of event amplitudes. C. The averaged mEPSCs recorded in one neurone illustrate that peak amplitude, rise and decay times of events was unaltered by ACBC. * P<0.05

Mentions: DCS has a relatively high efficacy at the co-agonist binding site (~85%). To determine if efficacy was an important determinant of the actions of DCS we tested the effects of a partial agonist, ACBC, with a much lower efficacy (~40%; [43]) on both the preNMDAr and the postNMDAr (see below). ACBC (1 mM) decreased the frequency of mEPSCs to 69.4±3.9%, from 1.7±0.3 Hz in control conditions to 1.2±0.2 Hz in the presence of the drug (P<0.05; n = 5; Fig 7A). Concurrently, there was no change in frequency distribution of event amplitudes (Fig 7B) or in mean amplitude (6.9±0.3 pA v 6.5±0.3 pA; see Fig 7C). Likewise, neither mEPSC rise time (2.18±0.14 ms v 2.38±0.06 ms) nor decay time (2.85±0.26 ms v 3.27±0.23 ms) was altered by ACBC, exemplified by the averaged (n = 20) events illustrated from one cell in Fig 7C.


Differential Effects of D-Cycloserine and ACBC at NMDA Receptors in the Rat Entorhinal Cortex Are Related to Efficacy at the Co-Agonist Binding Site.

Lench AM, Robson E, Jones RS - PLoS ONE (2015)

ACBC reduces preNMDAr activity.A. The histogram shows normalised frequency data for 5 neurones and indicates a significant decrease in frequency in the presence of the low-efficacy partial agonist. B. There was no concurrent change in frequency distribution of event amplitudes. C. The averaged mEPSCs recorded in one neurone illustrate that peak amplitude, rise and decay times of events was unaltered by ACBC. * P<0.05
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4507855&req=5

pone.0133548.g007: ACBC reduces preNMDAr activity.A. The histogram shows normalised frequency data for 5 neurones and indicates a significant decrease in frequency in the presence of the low-efficacy partial agonist. B. There was no concurrent change in frequency distribution of event amplitudes. C. The averaged mEPSCs recorded in one neurone illustrate that peak amplitude, rise and decay times of events was unaltered by ACBC. * P<0.05
Mentions: DCS has a relatively high efficacy at the co-agonist binding site (~85%). To determine if efficacy was an important determinant of the actions of DCS we tested the effects of a partial agonist, ACBC, with a much lower efficacy (~40%; [43]) on both the preNMDAr and the postNMDAr (see below). ACBC (1 mM) decreased the frequency of mEPSCs to 69.4±3.9%, from 1.7±0.3 Hz in control conditions to 1.2±0.2 Hz in the presence of the drug (P<0.05; n = 5; Fig 7A). Concurrently, there was no change in frequency distribution of event amplitudes (Fig 7B) or in mean amplitude (6.9±0.3 pA v 6.5±0.3 pA; see Fig 7C). Likewise, neither mEPSC rise time (2.18±0.14 ms v 2.38±0.06 ms) nor decay time (2.85±0.26 ms v 3.27±0.23 ms) was altered by ACBC, exemplified by the averaged (n = 20) events illustrated from one cell in Fig 7C.

Bottom Line: In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses.Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid.We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.

ABSTRACT
Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

No MeSH data available.


Related in: MedlinePlus