Abstracts

The hallmark of epilepsy is an increase of neuronal excitability. Paradoxically, however, this increase is commonly accompanied by diverse homeostatic mechanisms aimed at reducing neuronal excitability. One synapse thought to play a pivotal role in limbic epilepsy is dentate granule cell activation of CA3 pyramidal cells. Granule cell mossy fiber axons directly excite CA3 pyramidal cells by releasing glutamate from their giant boutons and indirectly inhibit the pyramidal cells by releasing glutamate from their filipodial terminals on to interneurons in stratum lucidum. We asked whether these distinct mossy fiber terminal specializations exhibited either pro-excitatory or homeostatic structural changes during the development of epilepsy. Changes in the ratio of excitatory to inhibitory neuron contacts could directly impact the development of epilepsy. Mice expressing green fluorescent protein (GFP) in dentate granule cell axons were used to examine granule cell pre-synaptic terminals in the kindling and the pilocarpine models of epilepsy. Giant mossy fiber boutons and mossy fiber filipodial terminals were examined in GFP-expressing mice 48 hours after pilocarpine-status epilepticus and 24 hours and 1 month after full kindling (defined as three class V seizures). Twenty-four hours after full kindling, dentate granule cell mossy fiber bouton area was increased by 49% (P[lt]0.05) and the number of filipodial extensions per mossy fiber bouton was increased by 61% (P[lt]0.05). One month after kindling, mossy fiber bouton area and number were indistinguishable from controls. A similar acute increase in mossy fiber bouton area (16%) and filipodia number (125%, P[lt]0.05) was observed 48 hours after status epilepticus. Increased numbers of giant mossy fiber bouton filipodial extensions in acute pilocarpine-treated and kindled mice suggest that the number of inhibitory interneurons contacted by a given dentate granule cell is increased. The predicted enhancement of feedforward inhibition in these animals may reflect compensatory homeostatic changes in response to recent seizure activity. Whether increased mossy fiber bouton area reflects a strengthening of granule cell[mdash]CA3 pyramidal cell contacts as well remains to be determined, however, the present results suggest that the series of structural modifications occurring during epileptogenesis involves both pathological changes likely to enhance seizure severity and compensatory changes aimed at stabilizing the system. (Supported by NS grant 17771.)