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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

The effect of DCS on the eNEPSC is reversed by D-serine.A. Averaged responses in one neurone show little effect of DCS on amplitude but a decrease in decay time. Cumulative addition of D-serine reverses the effect of DCS and increases both parameters to beyond control levels. B and C show pooled data for the two parameters in 7 neurones. * P<0.05.
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pone.0133548.g006: The effect of DCS on the eNEPSC is reversed by D-serine.A. Averaged responses in one neurone show little effect of DCS on amplitude but a decrease in decay time. Cumulative addition of D-serine reverses the effect of DCS and increases both parameters to beyond control levels. B and C show pooled data for the two parameters in 7 neurones. * P<0.05.

Mentions: To confirm whether the effect of DCS on eNEPSC kinetics was due to its partial agonist action we examined whether it was reversible by the full agonist. In these experiments a sub-maximal concentration (10 μM, n = 7) of DCS was applied, followed cumulatively by a saturating concentration of D-serine (1 mM). As noted above, DCS elicited a selective and significant decrease in decay time (to 84.7±2.9% of control). Following the addition of D-serine (Fig 6A and 6B), the reduction of eNEPSC decay time by DCS was reversed and increased to beyond control levels (109.8±2.1%; P<0.05). In addition, as with D-serine alone (see above), eNEPSC peak amplitude also increased (to 126.6±4.0%) in the presence of DCS plus D-serine (Fig 6A and 6C). The mean values for eNEPSC in control, DCS (10 μM) alone and DCS (10 μM) plus D-serine (1 mM) conditions were 391.0±26.6 ms, 333.0±28.7 ms and 430.1±31.5 ms, respectively, for decay time, and 123.5±23.9 pA, 124.8±26.2 pA and 160.1±34.3 pA, respectively, for 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)

The effect of DCS on the eNEPSC is reversed by D-serine.A. Averaged responses in one neurone show little effect of DCS on amplitude but a decrease in decay time. Cumulative addition of D-serine reverses the effect of DCS and increases both parameters to beyond control levels. B and C show pooled data for the two parameters in 7 neurones. * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133548.g006: The effect of DCS on the eNEPSC is reversed by D-serine.A. Averaged responses in one neurone show little effect of DCS on amplitude but a decrease in decay time. Cumulative addition of D-serine reverses the effect of DCS and increases both parameters to beyond control levels. B and C show pooled data for the two parameters in 7 neurones. * P<0.05.
Mentions: To confirm whether the effect of DCS on eNEPSC kinetics was due to its partial agonist action we examined whether it was reversible by the full agonist. In these experiments a sub-maximal concentration (10 μM, n = 7) of DCS was applied, followed cumulatively by a saturating concentration of D-serine (1 mM). As noted above, DCS elicited a selective and significant decrease in decay time (to 84.7±2.9% of control). Following the addition of D-serine (Fig 6A and 6B), the reduction of eNEPSC decay time by DCS was reversed and increased to beyond control levels (109.8±2.1%; P<0.05). In addition, as with D-serine alone (see above), eNEPSC peak amplitude also increased (to 126.6±4.0%) in the presence of DCS plus D-serine (Fig 6A and 6C). The mean values for eNEPSC in control, DCS (10 μM) alone and DCS (10 μM) plus D-serine (1 mM) conditions were 391.0±26.6 ms, 333.0±28.7 ms and 430.1±31.5 ms, respectively, for decay time, and 123.5±23.9 pA, 124.8±26.2 pA and 160.1±34.3 pA, respectively, for 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