Abstracts

Kynurenic acid (KYNA) is an endogenous antagonist of excitatory amino acid receptors that has anticonvulsant and neuroprotective effects. To determine the mechanism of action of glutamate receptor block by low concentrations of KYNA in the hippocampal area CA1, we used various stimulation protocols and found that KYNA block of glutamate receptors is activity dependent. Based on this finding, we decided to study the combined effects of KYNA and cyclothiazide (CTZ), to determine whether KYNA acts to stabilize the desensitized state.
Hippocampal coronal slices were prepared from adult (4-6 weeks) Sprague-Dawley rats. A stimulating electrode and an extracellular recording electrode or an intracellular recording electrode were placed in the stratum radiatum layer of the CA1. Evoked responses were established by stimulating for 20 [mu]sec every 5-60 sec. 100 [mu]M CTZ was used to prevent AMPAR desensitization. 5-50 [mu]M KYNA was added to the bath once a baseline response was established.
20 [mu]M KYNA blocks transmission in an activity dependent manner and in the presence of 100 [mu]M CTZ. In the absence of stimulation, 20 [mu]M KYNA applied for 20 minutes does not significantly affect evoked transmission. However, when Schaffer collateral synapses are periodically stimulated during a 20 minute application, 20 [mu]M KYNA completely blocks evoked transmission in a frequency dependent manner: when cells are stimulated every 5 seconds, transmission is blocked in 7.5 minutes; when cells are stimulated every 20 seconds, transmission is blocked in 20 minutes. When cells were pretreated for 20 or 40 minutes with 100 [mu]M CTZ, the baseline response increased by 30-40%. However, this pretreatment did not affect the time course or degree of KYNA block.
Low concentrations of KYNA produce an activity-dependent block of Schaffer collateral synapses that does not involve an interaction with the desensitized state of the glutamate receptors.
[Supported by: NIH]