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

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 o...

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Bibliographic Details
Published in:PloS one 2015-07, Vol.10 (7), p.e0133548-e0133548
Main Authors: Lench, Alex M, Robson, Emma, Jones, Roland S G
Format: Article
Language:English
Subjects:
Algorithms
Alzheimer's disease
Amino acids
Amino Acids, Cyclic - chemistry
Amyotrophic lateral sclerosis
Animal cognition
Animals
Astrocytes
Astrocytes - metabolism
Bicuculline - analogs & derivatives
Bicuculline - chemistry
Binding Sites
Brain
Carboxylic acids
Channel gating
Chemical properties
Cognitive ability
Cognitive enhancement
Cortex (entorhinal)
Cycloserine
Cycloserine - chemistry
D-Serine
Decay
Effectiveness
Electrical stimuli
Entorhinal Cortex - drug effects
Entorhinal Cortex - metabolism
Epilepsy
Ethics
Excitatory Postsynaptic Potentials - physiology
Female
Glutamate
Glutamic Acid - chemistry
Glutamic acid receptors (ionotropic)
Health aspects
Hippocampus - metabolism
Hostages
Hypotheses
Information processing
Ligands
Male
Memory tasks
N-Methyl-D-aspartic acid receptors
Neurons - metabolism
Patch-Clamp Techniques
Pharmacology
Pharmacy
Picrotoxin - chemistry
Presynaptic Terminals - metabolism
Psychiatry
Rats
Rats, Wistar
Receptors
Receptors, GABA-A - metabolism
Receptors, N-Methyl-D-Aspartate - metabolism
Rodents
Schizophrenia
Spatial analysis
Spatial memory
Strychnine - chemistry
Synapses
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0133548