Abstracts

RATIONALE: Metabotropic glutamate receptors may contribute significantly to epileptiform activity. CA3 bursting is a well recognized in-vitro model for pathological network synchronization, and resembles interictal spikes on human EEG. If it were possible to significantly decrease the burst frequency or stop the bursts, this may represent a potential therapeutic intervention. We examined the effect of a group 3 mGluR agonist, L-AP4, on CA3 bursting by evaluating the changes in the interburst interval.
METHODS: Hippocampal slices from 3-8 week old Sprague-Dawley rats were prepared in the usual manner. Slices were bathed in a modified ACSF solution with 3.3 mM KCl, 0.9 mM MgCl[sub]2[/sub], and 1.3 mM CaCl[sub]2[/sub], and CA3 bursting was induced by tetanic stimulation. Following baseline stabilization of the interburst interval, L-AP4 (1[mu]M) was added.
RESULTS: The addition of the L-AP4 resulted in an increase in the interburst interval within 15-30 minutes and eventual termination of the bursting within 40-140 minutes in a majority of slices (4 out of 5). This effect persisted even after washout of the L-AP4 for greater than 40-100 minutes. In 1 slice the interburst interval was 300% of control after washout, and in the other 4 slices there continued to be an evoked response, but there was no return of spontaneous bursting even with further tetanic stimulation.
CONCLUSIONS: This suggests that there is long term depression induced by L-AP4 in area CA3 of the rat hippocampus. Further studies with other mGluR agonists as well as assessment of the changes in the inhibitory and excitatory tone of the network are being evaluated to elucidate the mechanisms involved in causing this effect. Affecting the mGluR may represent a potential target for future therapeutic intervention.
Support: NIH