Fourth Conference on Epileptogenesis, May 23–26, 2007, Pisa, Italy

The Fourth Conference on Epileptogenesis was aimed at discussing new and controversial issues in the area of epileptogenesis research in the format of a workshop. Epileptogenesis is a particularly integrative field of research, in which experimental data and clinical evidence are brought together to provide insight into pathological plasticity phenomena and, more broadly, into the mechanisms of brain adaptation to environmental stimuli. The conference was opened by Lamberto Maffei, who presented an overview on the mechanisms regulating the postnatal development and plasticity of the rodent visual system. Visual system development and plasticity have been shown to depend largely on a proper sensory experience during early postnatal life. Recent studies have demonstrated the positive effects of environmental enrichment on the maturation and function of the visual system (Sale et al., 2007). These studies have profound implications for understanding both physiological and pathological development of CNS. The first session addressed the role of ion channels and transporters in epileptogenesis. Aristea Galanopoulou presented a study on the effects of the expression of KCC2 on GABA function in brain development. During development, GABAA receptors mediate depolarizing neuronal responses, whereas in the adult they are hyperpolarizing. The switch from depolarizing to hyperpolarizing GABAA receptor signaling is triggered through the developmental shift in the balance of intracellular chloride cotransporters. The maturation of GABAA signaling follows sex-specific patterns correlated with expression profiles of chloride cotransporter KCC2 (Galanopoulou, 2007), suggesting that GABAA receptor activation may be differentially regulated in males and females. This finding has particular implications in epilepsy, since GABAA receptor activation by antiepileptic drugs may differentially influence brain development in males and females. The role of calcium channels in epileptogenesis was discussed by Heinz Beck. In the pilocarpine model of temporal lobe epilepsy (TLE), a conversion from regular to burst firing (that is likely to play a role in TLE ictogenesis) was observed in hippocampal CA1 pyramidal neurons. Specific changes in the expression and properties of Cav3.2 T-type Ca2+ channel subunits were also detected (Su et al., 2002). Patchclamp analyses of CA1 neurons from pilocarpine-treated mice revealed that the burst-firing mode does not occur in mice lacking Cav3.2 channels. Moreover, the frequency and severity of chronic seizures, as well as the neuropathological sequelae were significantly attenuated in chronic epileptic Cav3.2 knockout mice, suggesting that Cav3.2 up-regulation after SE may contribute to initiation of seizure activity and neuronal cell death in chronic epilepsy. Potassium channel subunits mediate neuron repolarization following action potential discharge, and their mutations give rise to different types of seizure disorders in humans and in mouse models. The mechanisms underlying potassium channelopathies, discussed by Jeff Noebels, involve modified patterns of sustained repetitive firing properties in both excitatory cells and interneurons. Examples of mouse models include targeted deletion of the Kcna1, Kcnc2, Kcnq2/3, and the Kcnmb4 genes (mediating Kv1.1, Kv 3.2, Kv7.2/3, and BK currents, respectively). Since human epilepsy is often the product of complex or multigenic inheritance, it is crucial to analyze how mutations in more than one channel may interact. One new example of a digenic mouse model, involving Kcn1a and Cacna1a genes reveals multiple levels of physiological interaction leading to partial masking of the seizure phenotypes in these mutants (Glasscock et al., 2007). HCN1/HCN2 channel subunits responsible for hyperpolarization-activated current (Ih) are expressed at high density in dendrites and regulate overall dendritic excitability. As discussed by Daniel Johnston, Ih is partly active at resting potential and acts globally on dendritic inputs. These properties of Ih determine its ability to influence synaptic potentials in both hyperpolarizing and depolarizing membrane potential ranges. Temporal summation of excitatory synaptic potentials is reduced by Ih, regardless of the dendritic location of synapses. Long-term changes in the expression of Ih in pyramidal neurons of CA1 and entorhinal cortex have been demonstrated in acute and chronic models of TLE. Ih decreases and redistributes from dendrites to soma, significantly altering the oscillatory properties of pyramidal neurons, both in conditions of normal excitability (during long-term potentiation) and during epileptogenesis (Shah et al., 2004). Mutations in nicotinic receptor channels have also been associated with the epileptic phenotype. In particular, a missense mutation in the β2 subunit of neuronal nicotinic receptor (CHRNB2) was demonstrated in patients affected by autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a focal form of