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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 decreases both the amplitude and the decay time of the postsynaptic eNEPSC.A. Averaged responses for one neurone show a clear decrease in amplitude in the presence of ACBC, and the overlaid traces also indicate a substantial decrease in decay time. Amplitude scaling shows the latter effect very clearly. B and C. The graphs show pooled data for 7 neurones and illustrate the clear concentration-dependency for effects of ACBC on both parameters. * P<0.05.
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pone.0133548.g008: ACBC decreases both the amplitude and the decay time of the postsynaptic eNEPSC.A. Averaged responses for one neurone show a clear decrease in amplitude in the presence of ACBC, and the overlaid traces also indicate a substantial decrease in decay time. Amplitude scaling shows the latter effect very clearly. B and C. The graphs show pooled data for 7 neurones and illustrate the clear concentration-dependency for effects of ACBC on both parameters. * P<0.05.

Mentions: Like DCS, ACBC (0.03–1 mM, n = 7) substantially reduced the decay time of eNEPSCs (Fig 8A and 8C). The effect of ACBC was approaching maximal at 1 mM, where we recorded a mean reduction in eNEPSC decay time to 57.5±12.4% of control, with a change in mean from 524.8±102.96 ms to 249.0±26.5 ms (P<0.05). In contrast to DCS, however, ACBC also reduced the amplitude of eNEPSCs in a concentration-dependent manner (Fig 8A and 8B). The mean change in peak amplitude at 1 mM was to 62.0±5.9% of control (239.4±47.3 pA v 141.5±21.2 pA; P<0.05). Rise time was unaltered (31.3±4.2 ms v 30.3±5.3 ms). The averaged responses shown for one neurone in Fig 8A clearly show the change in amplitude, and when the responses were amplitude scaled and superimposed the reduced decay time was also obvious.


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 decreases both the amplitude and the decay time of the postsynaptic eNEPSC.A. Averaged responses for one neurone show a clear decrease in amplitude in the presence of ACBC, and the overlaid traces also indicate a substantial decrease in decay time. Amplitude scaling shows the latter effect very clearly. B and C. The graphs show pooled data for 7 neurones and illustrate the clear concentration-dependency for effects of ACBC on both parameters. * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133548.g008: ACBC decreases both the amplitude and the decay time of the postsynaptic eNEPSC.A. Averaged responses for one neurone show a clear decrease in amplitude in the presence of ACBC, and the overlaid traces also indicate a substantial decrease in decay time. Amplitude scaling shows the latter effect very clearly. B and C. The graphs show pooled data for 7 neurones and illustrate the clear concentration-dependency for effects of ACBC on both parameters. * P<0.05.
Mentions: Like DCS, ACBC (0.03–1 mM, n = 7) substantially reduced the decay time of eNEPSCs (Fig 8A and 8C). The effect of ACBC was approaching maximal at 1 mM, where we recorded a mean reduction in eNEPSC decay time to 57.5±12.4% of control, with a change in mean from 524.8±102.96 ms to 249.0±26.5 ms (P<0.05). In contrast to DCS, however, ACBC also reduced the amplitude of eNEPSCs in a concentration-dependent manner (Fig 8A and 8B). The mean change in peak amplitude at 1 mM was to 62.0±5.9% of control (239.4±47.3 pA v 141.5±21.2 pA; P<0.05). Rise time was unaltered (31.3±4.2 ms v 30.3±5.3 ms). The averaged responses shown for one neurone in Fig 8A clearly show the change in amplitude, and when the responses were amplitude scaled and superimposed the reduced decay time was also obvious.

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