Decreased Synaptic Strength Contributes to Prolonged Epileptiform Discharges Produced by Group I Metabotropic Glutamate Receptor Activation in Hippocampus
Abstract number :
1.011
Submission category :
Year :
2001
Submission ID :
679
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
P.A. Rutecki, M.D., Neurology, Neurosurgery, and Prog. in Neuroscience, U. of Wisconsin, Wm. Middleton VA Hospital, Madison, WI; U. Sayin, M.D., Ph.D., Neurology, U. of Wisconsin, Madison, WI
RATIONALE: Activation of group I metabotropic glutamate receptors (mGluR) produces prolonged synchronous epileptiform activity in the hippocampus. The group I mGluR agonist R,S-dihydroxyphenylglycine (DHPG) depresses synaptic transmission and decreases paired-pulse inhibition. To test the hypothesis that a reduction in synaptic strength promotes prolonged ictal-like discharges, we evaluated the effect of enhancement of synaptic transmission by 4-aminopyridine (4-AP) on both the epileptiform activity and depression of synaptic transmission produced by DHPG.
METHODS: Hippocampal slices were prepared from adult male Sprague Dawley rats and maintained in an interface chamber. Extracellular recordings were made from the CA3 region of hippocampal slices. Bath application of DHPG (100 [mu]M) for two hours induced recurrent, prolonged ([gt]3s) synchronous epileptiform discharges and the effect of 50 [mu]M 4-AP on the occurrence and duration of these discharges was assessed. Stimulation of stratum radiatum was used to assess the strength of synaptic transmission in producing a population spike and suppression of the population spike following a second paired stimulus. The paired-pulse response was measured in control conditions, after 30 minute exposure to DHPG, and with the co-application of 4-AP.
RESULTS: In the presence of 100 [mu]M DHPG 11 slices displayed ictal activity, and addition of 50 [mu]M 4-AP converted 7 of the slices to an interictal pattern. Following a 30 minutes exposure of 100 [mu]M DHPG, the evoked CA3 population spike was reduced by 35 [plusminus] 6%. Paired-pulse inhibition in the control condition was 43.8% [plusminus] 7% and was lost in the presence of DHPG with the paired population spike ratio changing to 118 [plusminus] 12% (n = 5). 4-AP reversed both the reduction of the initial population spike amplitude (69 [plusminus] 18% of control) and restored paired-pulse inhibition (59.2 [plusminus] 6%).
CONCLUSIONS: Group I mGluR activation produced a reduction in paired-pulse inhibition as well as depression of the first evoked population spike, yet results in prolonged epileptiform discharges in the hippocampal slice. Re-establishing excitability of the synaptic network by adding 4-AP to the bathing solution resulted in a suppression of prolonged discharges and a return of paired pulse inhibition. These results support the hypothesis that a reduction in synaptic strength by group I mGluR favors the development of prolonged epileptiform activity that characterizes seizures.
Support: VA research.