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.
Highlights
The entorhinal cortex (EC) acts as a crucial dynamic processer of information entering and leaving the hippocampus, controlling its interaction with the rest of the neuraxis
In a recent study we showed that the co-agonist site of the receptor is endogenously bound by D-serine
DCS, the partial agonist at the NMDA receptors (NMDArs) glycine/D-serine co-agonist binding site, had no detectable effect on the preNMDAr mediated tonic facilitation of glutamate release, whereas ACBC did induce a decrease in miniature excitatory postsynaptic currents (mEPSCs) frequency
Summary
The entorhinal cortex (EC) acts as a crucial dynamic processer of information entering and leaving the hippocampus, controlling its interaction with the rest of the neuraxis. Dysfunction of the EC and of EC-hippocampal interactions has been implicated in many pathological conditions, initiation and propagation of temporal lobe seizures and the cognitive abnormalities/decline associated with a variety of psychiatric/neurological disorders (including schizophrenia, bipolar and depressive disorders, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis etc.; see refs in [6]). This laboratory has a longstanding interest in control of neuronal activity and excitability in entorhinal networks. These effects could be relevant to putative therapeutic actions of the ligands
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