Abstracts

RATIONALE: Can long-term synaptic plasticity be utilized as an anticonvulsant strategy? Brief interictal discharges precede the onset of seizures, and may contribute to epileptogenesis due to high-frequency activation and consequent long-term potentiation of the strength of recurrent excitatory synapses. Partial blockade of NMDA receptors during synchronous network activation produces long-term decreases in synaptic strength and decreases the probability of future bursts.
METHODS: We used the CA3 region of the hippocampus as a model of network synchronization to test the effects of low-affinity NMDA antagonists on burst propagation. Spontaneous bursting of CA3 pyramidal neurons was induced by tetanic stimulation in the presence of 100-[mu]M picrotoxin and a modified ACSF (3.3 KCl, 1.3 CaCl[sub]2[/sub], 0.9 MgCl[sub]2[/sub]). Spontaneous interburst interval and burst duration were measured to compare the effects of SDZ-220-581, an orally active competitive NMDA antagonist (20-80 [mu]M), to D-APV (2.5-10 [mu]M) which we used in previous studies.
RESULTS: SDZ increased the interburst interval by 156-647% compared to control (n=5) but decreased burst duration by 15-25%. Similarly, D-APV increased the interburst interval by 38-194% compared to control and decreased burst duration by 11-22% (n=5). We could not wash SDZ due to its lipid solubility. When D-APV was washed, however, the interburst interval decreased but did not return to baseline values (124% of control, n=4 of 5).
CONCLUSIONS: These data suggest that a long-term alteration (e.g., long-term depression) of spontaneous burst probability occurs in the presence of low-affinity NMDA antagonists. This decrease in synchronous network activity may serve as a novel treatment for epilepsy.
Support: NIH and AES.