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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

D-serine increases the amplitude and decay time of eNEPSC in EC neurones.A. The traces show averaged eNEPSCs recorded in one neurone. A small, but clear, increase in amplitude by D-serine can be seen when the responses are overlaid. When control and D-serine responses were scaled to the same amplitude and overlaid, the prolongation of decay time is also apparent. B. The histograms show pooled normalised data for eNEPSC amplitude and decay times in the presence of D-serine in six neurones. * P<0.05.
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pone.0133548.g003: D-serine increases the amplitude and decay time of eNEPSC in EC neurones.A. The traces show averaged eNEPSCs recorded in one neurone. A small, but clear, increase in amplitude by D-serine can be seen when the responses are overlaid. When control and D-serine responses were scaled to the same amplitude and overlaid, the prolongation of decay time is also apparent. B. The histograms show pooled normalised data for eNEPSC amplitude and decay times in the presence of D-serine in six neurones. * P<0.05.

Mentions: As noted above, we have previously shown that the co-agonist site of the preNMDAr is essentially saturated (or very close to it) by endogenous D-serine [33]. However this did not appear to be the case with the postNMDArs at EC synapses. Thus, exogenous application of the full agonist, D-serine (100 μM, n = 6), increased the mean peak amplitude of eNEPSCs, from 205.5±40.7 pA to 240.3±50.1 pA (P<0.05), a normalised increase of 15.9±4.0% (Fig 3). The averaged responses from one study are shown in Fig 3A, where an increase in peak amplitude is evident. In addition, D-serine prolonged the decay time of the eNEPSC from 381.3±105.0 ms to 450.5±112.3 ms (Fig 3B). Scaling the traces to match control and drug treated amplitudes shows this prolongation of decay. In contrast, the rise time of the eNEPSC in control recordings was 36.2±8.0 ms, and this was unaltered (33.4±6.3 ms) in the presence of D-serine.


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)

D-serine increases the amplitude and decay time of eNEPSC in EC neurones.A. The traces show averaged eNEPSCs recorded in one neurone. A small, but clear, increase in amplitude by D-serine can be seen when the responses are overlaid. When control and D-serine responses were scaled to the same amplitude and overlaid, the prolongation of decay time is also apparent. B. The histograms show pooled normalised data for eNEPSC amplitude and decay times in the presence of D-serine in six neurones. * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4507855&req=5

pone.0133548.g003: D-serine increases the amplitude and decay time of eNEPSC in EC neurones.A. The traces show averaged eNEPSCs recorded in one neurone. A small, but clear, increase in amplitude by D-serine can be seen when the responses are overlaid. When control and D-serine responses were scaled to the same amplitude and overlaid, the prolongation of decay time is also apparent. B. The histograms show pooled normalised data for eNEPSC amplitude and decay times in the presence of D-serine in six neurones. * P<0.05.
Mentions: As noted above, we have previously shown that the co-agonist site of the preNMDAr is essentially saturated (or very close to it) by endogenous D-serine [33]. However this did not appear to be the case with the postNMDArs at EC synapses. Thus, exogenous application of the full agonist, D-serine (100 μM, n = 6), increased the mean peak amplitude of eNEPSCs, from 205.5±40.7 pA to 240.3±50.1 pA (P<0.05), a normalised increase of 15.9±4.0% (Fig 3). The averaged responses from one study are shown in Fig 3A, where an increase in peak amplitude is evident. In addition, D-serine prolonged the decay time of the eNEPSC from 381.3±105.0 ms to 450.5±112.3 ms (Fig 3B). Scaling the traces to match control and drug treated amplitudes shows this prolongation of decay. In contrast, the rise time of the eNEPSC in control recordings was 36.2±8.0 ms, and this was unaltered (33.4±6.3 ms) in the presence of D-serine.

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