Epilepsia, 48(Suppl. 5):131–139, 2007 Blackwell Publishing, Inc. C  International League Against Epilepsy Hyperexcitability of the CA1 Hippocampal Region during Epileptogenesis ∗ †Lynda El-Hassar, ∗ †Monique Esclapez, and ∗ †Christophe Bernard ∗ INMED-INSERM U29, Universit´ e de la M´ editerran´ ee, Marseille, France Summary: Temporal Lobe Epilepsy (TLE) is often preceded by a latent (seizure-free) period during which complex network reorganizations occur. In experimental epilepsy, network hyper- excitability is already present during the latent period, suggest- ing a modification of information processing. The purpose of this study was to assess the input/output relationship in the hippocam- pal CA1 region during epileptogenesis. Field recordings in strata pyramidale and radiatum were used to measure the output of CA1 pyramidal cells as a function of the synaptic inputs they receive following the stimulation of Shaffer collaterals in slices obtained from sham and pilocarpine-treated animals during the latent and chronic periods. We show that there is a transient increase of the input and output field responses during the latent period as compared to sham and epileptic animals. The coupling between excitatory inputs and cell firing was also increased during the la- tent period. This increase persisted in epileptic animals, although to a lesser extent. We also confirm that paired-pulse facilitation occurs before the chronic phase. The present data further sup- port the view that hyperexcitability is present at an early stage of epileptogenesis. Network output is more facilitated during the latent than during the chronic period. Hyperexcitability may participate to epileptogenesis, but it is not sufficient in itself to produce seizures. Key Words: Epilepsy—Hippocampus— Model. Temporal Lobe Epilepsy (TLE), the most common form of partial epilepsy in adults (Engel, Jr., 1996), is often pre- ceded by a latent (seizure-free) period following an ini- tial insult (Wieser, 2004) before the occurrence of spon- taneous recurrent seizure (chronic stage). In experimental epilepsy, including the pilocarpine (Cossart et al., 2001), kainate (Bragin et al., 1999; Wu and Leung, 2003), self- sustaining limbic status epilepticus (Mangan and Loth- man, 1996; Gorter et al., 2002) models, the CA1 region of the hippocampus is hyperexcitable during the chronic stage. Such hyperexcitability may constitute a permissive factor for the genesis and/or the propagation of epilep- tic seizures. Various nonexclusive mechanisms have been proposed to explain network hyperexcitability, includ- ing an increased glutamatergic drive as a result of CA1 pyramidal cell (PC) axonal sprouting (Perez et al., 1996; Esclapez et al., 1999; Smith and Dudek, 2001; Lehmann et al., 2001), a decreased GABAergic drive induced by interneurons loss (Smith and Dudek, 2001; Houser and Esclapez, 1996; Dinocourt et al., 2003), and increased in- Address correspondence and reprint requests to Christophe Bernard, Ph.D., INSERM U751, Facult´ e de M´ edecine Timone, 27 Bd Jean Moulin, 13385 Marseille cedex 05, France. E-mail: christophe.bernard@ medecine.univ.mrs.fr †Present address INSERM U751, Universit´ e de la M´ editerran´ ee, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France. doi: 10.1111/j.1528-1167.2007.01301.x trinsic cell excitability (Su et al., 2002; Bernard et al., 2004). Some of these modifications occur very early dur- ing the latent period, probably as a direct consequence of the initial status epilepticus, in particular the loss of both somatic and dendrite projecting GABAergic interneurons (Dinocourt et al., 2003), resulting in a decreased GABAer- gic drive in PC dendrites and somata (El-Hassar et al., 2007). In contrast, PC axonal sprouting and increased ex- citatory drive appear to be specific to the chronic period (Smith and Dudek, 2001). At the network level, these early alterations in the GABAergic circuitry during the latent are associated to CA1 PC burst discharges following affer- ent stimulations (Mangan and Bertram, 1998; Smith and Dudek, 2001) and paired-pulse facilitation (Gorter et al., 2002). Such increased excitability persists and is even am- plified during the chronic stage (Mangan and Bertram, 1998; Smith and Dudek, 2001; Gorter et al., 2002 ). Some of these features are also found in the dentate gyrus and the entorhinal cortex (Hellier and Dudek, 1999; Wuarin and Dudek, 2001; Gorter et al., 2002; Kobayashi and Buck- master, 2003; Kobayashi et al., 2003; Kumar and Buck- master, 2006). Building on these studies, we wished to determine the ontogeny of the input/output relationship of CA1 PCs during epileptogenesis. Using simultaneous extracellular recordings in vitro in the PC layer and the stratum ra- diatum, we measured field excitatory synaptic potential 131