D‐Cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices

Abstract

1. The glycine-binding site of the glutamatergic N-methyl-d-aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonist d-cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials. 2. We showed that DCS facilitated NMDAr-mediated synaptic potentials. In addition, we found that the magnitude of NMDAr-dependent long-term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered. 3. We found that DCS decreased neurotransmission mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by the gamma-aminobutyric acid GABAA antagonist bicuculline, but was antagonized by the glycine antagonist strychnine. 4. These results, therefore, show opposite effects of DCS on NMDA and non-NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long-term synaptic plasticity that may support the DCS-induced enhanced cognitive performances.