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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 rescues the abolition of the eNEPSC from inhibition by DCKA.A. Averaged synaptic responses from one neurone show abolition of the eNEPSC by the co-agonist site antagonist, DCKA. Subsequent addition of DCS at 2 mM partly restored the response; increasing the partial agonist concentration to 10 mM had a substantially greater restorative action. The histograms show the pooled normalised data for amplitude (B) and decay time (C) in 8 neurones. The restoration of the eNEPSC was partial, but it is noteworthy that the peak amplitude with DCKA plus DCS at 10 mM was not significantly different to that in control conditions. * P<0.05; ** P<0.01.
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pone.0133548.g005: DCS rescues the abolition of the eNEPSC from inhibition by DCKA.A. Averaged synaptic responses from one neurone show abolition of the eNEPSC by the co-agonist site antagonist, DCKA. Subsequent addition of DCS at 2 mM partly restored the response; increasing the partial agonist concentration to 10 mM had a substantially greater restorative action. The histograms show the pooled normalised data for amplitude (B) and decay time (C) in 8 neurones. The restoration of the eNEPSC was partial, but it is noteworthy that the peak amplitude with DCKA plus DCS at 10 mM was not significantly different to that in control conditions. * P<0.05; ** P<0.01.

Mentions: To confirm that DCS was exerting its effects at the co-agonist site of the NMDAr we determined the effect of combined administration of the co-agonist site antagonist, DCKA. We showed earlier that DCKA applied at 100μM abolished eNEPSC and this is illustrated again in Fig 5A. In the presence of the antagonist, subsequent addition of 1 mM DCS (n = 3) had no restorative effects on the eNEPSC (not shown). However, at higher concentrations, DCS rescued eNEPSC amplitude in a concentration dependent manner (Fig 5A and 5B; n = 8). As before, eNEPSCs were essentially abolished by DCKA, but in its continued presence the amplitude of the evoked response was increased by the partial agonist to reach a mean of 42.4±7.3% of control at 2 mM and 73.9±13.6% of control with cumulative addition to 10 mM (Fig 5A and 5B). The decay time of the restored responses was 26.1±2.9% of control (pre-DCKA) at 2 mM and 34.4±1.8% at 10 mM. Although the responses were not apparently fully recovered with 10 mM DCS, the eNEPSC at this concentration had a mean absolute amplitude of 188.4±101.9 pA, which was not significantly different to that before DCKA (217.6±64.5 pA). Thus, it seems likely that the effects of DCS alone on eNEPSCs were due to agonistic actions at the postNMDAr co-agonist binding site.


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 rescues the abolition of the eNEPSC from inhibition by DCKA.A. Averaged synaptic responses from one neurone show abolition of the eNEPSC by the co-agonist site antagonist, DCKA. Subsequent addition of DCS at 2 mM partly restored the response; increasing the partial agonist concentration to 10 mM had a substantially greater restorative action. The histograms show the pooled normalised data for amplitude (B) and decay time (C) in 8 neurones. The restoration of the eNEPSC was partial, but it is noteworthy that the peak amplitude with DCKA plus DCS at 10 mM was not significantly different to that in control conditions. * P<0.05; ** P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133548.g005: DCS rescues the abolition of the eNEPSC from inhibition by DCKA.A. Averaged synaptic responses from one neurone show abolition of the eNEPSC by the co-agonist site antagonist, DCKA. Subsequent addition of DCS at 2 mM partly restored the response; increasing the partial agonist concentration to 10 mM had a substantially greater restorative action. The histograms show the pooled normalised data for amplitude (B) and decay time (C) in 8 neurones. The restoration of the eNEPSC was partial, but it is noteworthy that the peak amplitude with DCKA plus DCS at 10 mM was not significantly different to that in control conditions. * P<0.05; ** P<0.01.
Mentions: To confirm that DCS was exerting its effects at the co-agonist site of the NMDAr we determined the effect of combined administration of the co-agonist site antagonist, DCKA. We showed earlier that DCKA applied at 100μM abolished eNEPSC and this is illustrated again in Fig 5A. In the presence of the antagonist, subsequent addition of 1 mM DCS (n = 3) had no restorative effects on the eNEPSC (not shown). However, at higher concentrations, DCS rescued eNEPSC amplitude in a concentration dependent manner (Fig 5A and 5B; n = 8). As before, eNEPSCs were essentially abolished by DCKA, but in its continued presence the amplitude of the evoked response was increased by the partial agonist to reach a mean of 42.4±7.3% of control at 2 mM and 73.9±13.6% of control with cumulative addition to 10 mM (Fig 5A and 5B). The decay time of the restored responses was 26.1±2.9% of control (pre-DCKA) at 2 mM and 34.4±1.8% at 10 mM. Although the responses were not apparently fully recovered with 10 mM DCS, the eNEPSC at this concentration had a mean absolute amplitude of 188.4±101.9 pA, which was not significantly different to that before DCKA (217.6±64.5 pA). Thus, it seems likely that the effects of DCS alone on eNEPSCs were due to agonistic actions at the postNMDAr co-agonist binding site.

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