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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

DCS decreases the decay time of eNEPSCs.A. Averaged traces for one neurone are shown for control and in the presence of 30 μM DCS. The overlaid traces clearly show that the amplitude of the eNEPSC is unaffected whereas the response decay is substantially accelerated. The graphs show pooled data of cumulative concentration response curves for normalised data in six neurones for peak amplitude (B) and decay time (C). DCS failed to significantly alter peak amplitude at any concentration, but produced a concentration-dependent decrease in eNEPSC decay time. * P<0.05; ** P<0.01.
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pone.0133548.g004: DCS decreases the decay time of eNEPSCs.A. Averaged traces for one neurone are shown for control and in the presence of 30 μM DCS. The overlaid traces clearly show that the amplitude of the eNEPSC is unaffected whereas the response decay is substantially accelerated. The graphs show pooled data of cumulative concentration response curves for normalised data in six neurones for peak amplitude (B) and decay time (C). DCS failed to significantly alter peak amplitude at any concentration, but produced a concentration-dependent decrease in eNEPSC decay time. * P<0.05; ** P<0.01.

Mentions: We next examined the effect of DCS (1–30 μM), a partial agonist at the co-agonist site, on eNEPSCs in 6 neurones. In contrast to D-serine, DCS did not significantly alter the amplitude of eNEPSCs at any concentration tested, with a small reduction of around 8% recorded at the highest concentration (30 μM) tested (190.9±53.8 pA v 160.6±35.3 pA; Fig 4A and 4B). Likewise, DCS had no effect on rise time (44.7±9.3 ms v 52.3±15.1 ms at 30 μM) of eNEPSCs. However, the drug elicited a clear, concentration-dependent decrease in decay time (Fig 4A and 4C). This was evident and significant even at low concentrations and the effect had an IC50 of 2.1 μM. The maximum normalised reduction (at 30 μM) was to 68.1±5.9% of control, corresponding to a decrease in mean decay time from 593.8±94.6 ms to 417.4±78.7 ms (P<0.01). The exemplar experiment shown in Fig 4A illustrates the lack of change in amplitude, but overlay of the records reveals the much faster decay in the presence of DCS.


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)

DCS decreases the decay time of eNEPSCs.A. Averaged traces for one neurone are shown for control and in the presence of 30 μM DCS. The overlaid traces clearly show that the amplitude of the eNEPSC is unaffected whereas the response decay is substantially accelerated. The graphs show pooled data of cumulative concentration response curves for normalised data in six neurones for peak amplitude (B) and decay time (C). DCS failed to significantly alter peak amplitude at any concentration, but produced a concentration-dependent decrease in eNEPSC decay time. * P<0.05; ** P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133548.g004: DCS decreases the decay time of eNEPSCs.A. Averaged traces for one neurone are shown for control and in the presence of 30 μM DCS. The overlaid traces clearly show that the amplitude of the eNEPSC is unaffected whereas the response decay is substantially accelerated. The graphs show pooled data of cumulative concentration response curves for normalised data in six neurones for peak amplitude (B) and decay time (C). DCS failed to significantly alter peak amplitude at any concentration, but produced a concentration-dependent decrease in eNEPSC decay time. * P<0.05; ** P<0.01.
Mentions: We next examined the effect of DCS (1–30 μM), a partial agonist at the co-agonist site, on eNEPSCs in 6 neurones. In contrast to D-serine, DCS did not significantly alter the amplitude of eNEPSCs at any concentration tested, with a small reduction of around 8% recorded at the highest concentration (30 μM) tested (190.9±53.8 pA v 160.6±35.3 pA; Fig 4A and 4B). Likewise, DCS had no effect on rise time (44.7±9.3 ms v 52.3±15.1 ms at 30 μM) of eNEPSCs. However, the drug elicited a clear, concentration-dependent decrease in decay time (Fig 4A and 4C). This was evident and significant even at low concentrations and the effect had an IC50 of 2.1 μM. The maximum normalised reduction (at 30 μM) was to 68.1±5.9% of control, corresponding to a decrease in mean decay time from 593.8±94.6 ms to 417.4±78.7 ms (P<0.01). The exemplar experiment shown in Fig 4A illustrates the lack of change in amplitude, but overlay of the records reveals the much faster decay in the presence of DCS.

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