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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

Effects of DCS on preNMDAr activity.A. The histograms show average normalised changes in frequency of mEPSCs with DCS and 2-AP5 in six neurones. DCS was without effect whereas subsequent, cumulative addition of 2-AP5 reduced frequency by ~30%. B. The graphs show that the frequency distribution of amplitudes of mEPSCs was unaltered by either antagonist. C. Average mEPSCs (n = 20) in one neurone showing the lack of change in amplitude, rise or decay time with either drug. * P<0.05.
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pone.0133548.g001: Effects of DCS on preNMDAr activity.A. The histograms show average normalised changes in frequency of mEPSCs with DCS and 2-AP5 in six neurones. DCS was without effect whereas subsequent, cumulative addition of 2-AP5 reduced frequency by ~30%. B. The graphs show that the frequency distribution of amplitudes of mEPSCs was unaltered by either antagonist. C. Average mEPSCs (n = 20) in one neurone showing the lack of change in amplitude, rise or decay time with either drug. * P<0.05.

Mentions: In the first set of experiments we determined the effect of the partial agonist, DCS, using the frequency of mEPSCs mediated by AMPAr as a reporter for glutamate release and, hence, preNMDAr activity [30]. DCS (300 μM) had no observable effect on mEPSC frequency in 6 neurones (Fig 1A). In control conditions, mean frequency was 0.65±0.29 Hz and this was almost identical in the presence of DCS (0.62±0.32 Hz). However, subsequent addition of 2-AP5 (50 μM) reduced the frequency of mEPSCs to 0.47±0.23 Hz, a decrease to 71.1±4.3% of control (Fig 1A) confirming that preNMDArs were operative at these synapses to tonically facilitate glutamate release. DCS failed to alter either the mean amplitude of mEPSCs (7.0±0.4 pA v 6.9±0.4 pA), or their frequency distribution (Fig 1B and 1C), and these parameters were also unchanged with further addition of 2-AP5 (mean amplitude 6.9±0.4pA). Likewise, decay kinetics (control 2.22±0.32 ms) were unaltered, either by DCS alone (1.98±0.30 ms) or DCS plus 2-AP5 (2.00±0.28 ms). Finally, neither mEPSC rise time nor baseline holding current was altered in any situation (not shown). The lack of effect on kinetics is clearly shown by the averaged mEPSCs shown in Fig 1C. DCS was also tested, at a lower concentration (100 μM; n = 6) and again had no observable effect on mEPSC parameters (e.g. frequency 0.55±0.14 Hz in control and 0.53±0.19 Hz in DCS; other data not shown). These data confirm that glutamate release was subject to tonic facilitation by preNMDAr, but, at the concentrations tested, the partial agonist at the co-agonist binding site did not alter the effects of presynaptic receptor activation.


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)

Effects of DCS on preNMDAr activity.A. The histograms show average normalised changes in frequency of mEPSCs with DCS and 2-AP5 in six neurones. DCS was without effect whereas subsequent, cumulative addition of 2-AP5 reduced frequency by ~30%. B. The graphs show that the frequency distribution of amplitudes of mEPSCs was unaltered by either antagonist. C. Average mEPSCs (n = 20) in one neurone showing the lack of change in amplitude, rise or decay time with either drug. * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133548.g001: Effects of DCS on preNMDAr activity.A. The histograms show average normalised changes in frequency of mEPSCs with DCS and 2-AP5 in six neurones. DCS was without effect whereas subsequent, cumulative addition of 2-AP5 reduced frequency by ~30%. B. The graphs show that the frequency distribution of amplitudes of mEPSCs was unaltered by either antagonist. C. Average mEPSCs (n = 20) in one neurone showing the lack of change in amplitude, rise or decay time with either drug. * P<0.05.
Mentions: In the first set of experiments we determined the effect of the partial agonist, DCS, using the frequency of mEPSCs mediated by AMPAr as a reporter for glutamate release and, hence, preNMDAr activity [30]. DCS (300 μM) had no observable effect on mEPSC frequency in 6 neurones (Fig 1A). In control conditions, mean frequency was 0.65±0.29 Hz and this was almost identical in the presence of DCS (0.62±0.32 Hz). However, subsequent addition of 2-AP5 (50 μM) reduced the frequency of mEPSCs to 0.47±0.23 Hz, a decrease to 71.1±4.3% of control (Fig 1A) confirming that preNMDArs were operative at these synapses to tonically facilitate glutamate release. DCS failed to alter either the mean amplitude of mEPSCs (7.0±0.4 pA v 6.9±0.4 pA), or their frequency distribution (Fig 1B and 1C), and these parameters were also unchanged with further addition of 2-AP5 (mean amplitude 6.9±0.4pA). Likewise, decay kinetics (control 2.22±0.32 ms) were unaltered, either by DCS alone (1.98±0.30 ms) or DCS plus 2-AP5 (2.00±0.28 ms). Finally, neither mEPSC rise time nor baseline holding current was altered in any situation (not shown). The lack of effect on kinetics is clearly shown by the averaged mEPSCs shown in Fig 1C. DCS was also tested, at a lower concentration (100 μM; n = 6) and again had no observable effect on mEPSC parameters (e.g. frequency 0.55±0.14 Hz in control and 0.53±0.19 Hz in DCS; other data not shown). These data confirm that glutamate release was subject to tonic facilitation by preNMDAr, but, at the concentrations tested, the partial agonist at the co-agonist binding site did not alter the effects of presynaptic receptor activation.

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