EPILEPTIFORM ACTIVITY STRENGTHENS EXCITATORY SYNAPSES

Mathias Abegg
Brain Research Institute, University of Zürich, Zürich, Switzerland.

In the hippocampus coincident pre- and postsynaptic activity leads to the enhancement of synaptic strength via insertion of AMPA-type glutamate receptors, a phenomenon known as long-term potentiation (LTP). A similar pattern of activity can be observed during epileptic burst discharges. Whether such epileptiform activity affects the strength of CA3-CA1 synapses is as yet unknown. To study this, I treated organotypic hippocampal slice cultures overnight with bicuculline-methochloride, a specific blocker of inhibitory GABAA receptors. This treatment induced repetitive burst discharges at about 0.05 Hz. Recordings of AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) revealed a significant increase in both amplitude and frequency of mEPSCs after bursting overnight. Also the ratio of evoked AMPA- versus NMDA-current was higher in bicuculline-treated cultures, suggesting that bursting leads to AMPA receptors insertion into silent (NMDA only) synapses. The paired-pulse ratio of evoked AMPA receptor-mediated currents was not affected by epileptiform activity, suggesting that the probability of vesicular neurotransmitter release was not altered. Furthermore I assessed whether the phenomena induced by bursting activity are NMDA receptor-dependent, as is LTP. Application of an NMDA receptor antagonist during bursting prevented the above changes but failed to affect bursting itself. Finally I tested whether LTP itself is affected by bursting activity. Measurements of excitatory field responses upon application of a classical LTP protocol showed, that synapses from cultures that have bursted overnight can not be further potentiated whereas normal LTP was observed in control cultures. This suggests that bursting leads to a saturating potentiation of synapses. In conclusion our data indicate that bursting activity leads to an NMDA receptor dependent AMPA receptor insertion into virtually all plastic CA3-CA1 synapses. Provided similar events occur in vivo, the above observations may play a role in the genesis and progression of epilepsy: Epileptic activity may strengthen excitatory synapses and lead to an imbalance of excitation over inhibition, thereby making a hippocampal network that has already experienced one epileptic seizure particularly susceptible for further seizures. Our findings also provide a simple possible explanation for amnesia accompanying generalized epileptic seizures: Since virtually all synapses may be maximally potentiated, the interplay between LTP and long term depression, thought to underlie learning, can no longer function properly.