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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

eNEPSCs in entorhinal neurones.The traces show voltage clamp recordings of eNEPSCs evoked in layer II neurones in the medial EC. Each response is the average of at least 5 events. A. The addition of the competitive antagonist, 2-AP5 abolished the eNEPSC. B. Likewise, application of the co-agonist site antagonist, DCKA, was also able to abolish the eNEPSC. C. The decay of n averaged (n = 8) eNEPSC was fitted with either a mono- (top) or bi-exponential function. Whilst R2 values show an excellent fit to a biexponential decay, the mono-exponential fit was almost as good. The slow decay corresponding to tau-2 in the biexponential fit was extremely variable from neurone to neurone, and precluded meaningful analysis. Since the mono-exponential fit was excellent, in all further studies we assumed a mono-exponential decay.
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pone.0133548.g002: eNEPSCs in entorhinal neurones.The traces show voltage clamp recordings of eNEPSCs evoked in layer II neurones in the medial EC. Each response is the average of at least 5 events. A. The addition of the competitive antagonist, 2-AP5 abolished the eNEPSC. B. Likewise, application of the co-agonist site antagonist, DCKA, was also able to abolish the eNEPSC. C. The decay of n averaged (n = 8) eNEPSC was fitted with either a mono- (top) or bi-exponential function. Whilst R2 values show an excellent fit to a biexponential decay, the mono-exponential fit was almost as good. The slow decay corresponding to tau-2 in the biexponential fit was extremely variable from neurone to neurone, and precluded meaningful analysis. Since the mono-exponential fit was excellent, in all further studies we assumed a mono-exponential decay.

Mentions: In the presence of AMPAr and GABAA receptor blockers, stimulation in the EC lateral to the recording site elicited large, slowly decaying EPSCs in layer II neurones voltage clamped at +40 mV. These were abolished by 2-AP5, confirming that they were mediated by postNMDArs (Fig 2A; n = 3). In addition, we also tested the effect of a high concentration (100 μM, determined to be close to Emax) of the co-agonist site competitive antagonist, DCKA (Fig 2B; n = 3). This also rapidly (<5 minutes) abolished the eNEPSC and confirmed that the co-agonist site of the postNMDAr was endogenously activated. We have previously examined other aspects of the pharmacology of these eNEPSCs in entorhinal neurones and determined that they are likely to be mediated by triheteromeric GluN1-GluN2A-GluN2B receptors [8]. The slow decay of eNEPSC in other neurones has been shown to be bi-exponential [42] so we looked at this possibility in our neurones. We found that the decay of the eNEPSC in layer II was only marginally better described by biexponential decay kinetics, compared to monoexponential (Fig 2C). The decay time constants were variable from neurone to neurone, particularly in the case of the slow phase of decay, where the variability precluded any meaningful analysis, so in all studies we have assumed monoexponential decay, and compared the time taken to decline to 37% of peak amplitude.


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)

eNEPSCs in entorhinal neurones.The traces show voltage clamp recordings of eNEPSCs evoked in layer II neurones in the medial EC. Each response is the average of at least 5 events. A. The addition of the competitive antagonist, 2-AP5 abolished the eNEPSC. B. Likewise, application of the co-agonist site antagonist, DCKA, was also able to abolish the eNEPSC. C. The decay of n averaged (n = 8) eNEPSC was fitted with either a mono- (top) or bi-exponential function. Whilst R2 values show an excellent fit to a biexponential decay, the mono-exponential fit was almost as good. The slow decay corresponding to tau-2 in the biexponential fit was extremely variable from neurone to neurone, and precluded meaningful analysis. Since the mono-exponential fit was excellent, in all further studies we assumed a mono-exponential decay.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507855&req=5

pone.0133548.g002: eNEPSCs in entorhinal neurones.The traces show voltage clamp recordings of eNEPSCs evoked in layer II neurones in the medial EC. Each response is the average of at least 5 events. A. The addition of the competitive antagonist, 2-AP5 abolished the eNEPSC. B. Likewise, application of the co-agonist site antagonist, DCKA, was also able to abolish the eNEPSC. C. The decay of n averaged (n = 8) eNEPSC was fitted with either a mono- (top) or bi-exponential function. Whilst R2 values show an excellent fit to a biexponential decay, the mono-exponential fit was almost as good. The slow decay corresponding to tau-2 in the biexponential fit was extremely variable from neurone to neurone, and precluded meaningful analysis. Since the mono-exponential fit was excellent, in all further studies we assumed a mono-exponential decay.
Mentions: In the presence of AMPAr and GABAA receptor blockers, stimulation in the EC lateral to the recording site elicited large, slowly decaying EPSCs in layer II neurones voltage clamped at +40 mV. These were abolished by 2-AP5, confirming that they were mediated by postNMDArs (Fig 2A; n = 3). In addition, we also tested the effect of a high concentration (100 μM, determined to be close to Emax) of the co-agonist site competitive antagonist, DCKA (Fig 2B; n = 3). This also rapidly (<5 minutes) abolished the eNEPSC and confirmed that the co-agonist site of the postNMDAr was endogenously activated. We have previously examined other aspects of the pharmacology of these eNEPSCs in entorhinal neurones and determined that they are likely to be mediated by triheteromeric GluN1-GluN2A-GluN2B receptors [8]. The slow decay of eNEPSC in other neurones has been shown to be bi-exponential [42] so we looked at this possibility in our neurones. We found that the decay of the eNEPSC in layer II was only marginally better described by biexponential decay kinetics, compared to monoexponential (Fig 2C). The decay time constants were variable from neurone to neurone, particularly in the case of the slow phase of decay, where the variability precluded any meaningful analysis, so in all studies we have assumed monoexponential decay, and compared the time taken to decline to 37% of peak amplitude.

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