Abstracts

Previous reports have shown that mGluR-mediated inhibition within the dentate is altered after pilocarpine (PILO)-induced status epilepticus. Whether these changes contribute to the development of the disease (i.e., occur during the latent period), however, remains an important and unresolved issue.
Field excitatory postsynaptic potentials (fEPSPs) were recorded in the lateral (LPP) and medial perforant path (MPP) simultaneously in adult mouse hippocampal slices. Paired stimuli (0.1ms duration, 150ms interpulse interval) were delivered to help differentiate MPP (paired-pulse depression) from LPP (paired-pulse facilitation) responses and to assess drug-induced increases in the paired-pulse ratio that are consistent with a presynaptic site of action. fEPSP slopes (10-90%) were measured in control and PILO-treated mice in response to selective group II and group III agonists.
Application of the selective group II mGluR agonist DCG-IV (300nM) reversibly depressed the fEPSP slopes in both the LPP (-30 [plusmn] 2%, n=7) and the MPP (-45 [plusmn] 3%, n=7) in control mice; by comparison, PILO-treated animals showed similar levels of inhibition within the LPP (-25 [plusmn] 2%, n=10) but inhibition within the MPP was significantly enhanced (-61 [plusmn] 4%, n=10; p[lt]0.01, ANOVA). Treatment with a selective group III agonist (L-AP4, 600uM) reversibly depressed fEPSP slopes in both the LPP (-40 [plusmn] 5%, n=7) and the MPP (-14 [plusmn] 5%, n=7) in controls; in PILO-treated animals, L-AP4 produced the same level of inhibition as was observed in controls (-43 [plusmn] 2%, n=10), however inhibition within the MPP was markedly diminished (-4 [plusmn] 2%, n=10; p[lt]0.05, ANOVA). The specific mGluR8 receptor agonist S-3,4-DCPG (3uM) reversibly inhibited the LPP (-31 [plusmn] 2%, n=11) but not MPP in control animals; there were no differences for PILO-treated mice (LPP only, -28 [plusmn] 2%, n=9).
In the MPP, mGluR7-mediated inhibition was reduced 3-9 days after PILO, whereas mGluR2/3-mediated inhibition was enhanced. In the LPP, there were no significant changes in mGluR-mediated inhibition after PILO treatment. Consistent with previous work, these data indicate that mGluR-mediated inhibition within the dentate is altered prior to the onset of spontaneous recurrent seizures. Future studies are required to decipher whether these changes are compensatory or contribute to epileptogenesis.
[Supported by: The Charlie Foundation (KJB), NINDS grant NS043032 (KJB), and the NINDS (RJD).]