The mechanisms that underlie GFOs in epileptogenic conditions at early stages of development contrast with those arising in physiological MEK inhibitor conditions.

Several observations suggest that spontaneous GFOs are not present in developing networks. In rat pups, high-frequency (120–180 Hz) oscillations are observed in vivo in the hippocampus after the end of the second postnatal week (Buhl and Buzsáki, 2005). Moreover, various in vitro GFO-generating procedures or agents, such as bath application of the ACh receptor agonist carbachol of intact cortex of newborn rats (Kilb and Luhmann, 2003) or high-frequency stimulation of CA1 afferents in rat hippocampal slices (Ruusuvuori et al., 2004), failed Bosutinib manufacturer to generate GFOs during the first postnatal week. Because physiological GFOs are largely driven by glutamate in

mature networks (Bartos et al., 2007, Fisahn et al., 1998, Traub et al., 1998 and Whittington and Traub, 2003), these observations are consistent with the delayed maturation of glutamatergic synapses shown in a wide range of brain structures (Gozlan and Ben-Ari, 2003). As suggested previously (Traub et al., 1998), developing networks would lack the critical density of functional glutamatergic synapses required for these oscillatory activities. However, GFOs can emerge in epileptogenic conditions, signaling a pathological state. We showed that AMPA receptor activation is not necessary for GFO expression, and the glutamatergic drive always follows the GABAergic one in all neuron types. This is also consistent with other findings showing that synchronization of GABA neurons can occur in the absence of fast glutamatergic signaling via depolarizing GABA (Avoli and Perreault, 1987 and Michelson and Wong, 1991). Furthermore, this is also in agreement with the tetanic model of GFOs that displays comparable GABA mechanisms to the low Mg2+ model (Fujiwara-Tsukamoto et al., 2006), because it also

requires a depolarizing GABA action (Köhling et al., 2000), which is due to intracellular chloride accumulation during recurrent seizures (Dzhala et al., 2010). Although very high-frequency oscillations Methisazone (HFOs in the ripples: 140–200 Hz; fast ripples: 200–500 Hz) can be recorded in adult epileptic networks in vitro (Khosravani et al., 2005 and Traub et al., 2001) and in vivo (Jirsch et al., 2006), the GFOs recorded in our conditions never reached such frequencies during the first postnatal week, probably reflecting the immature stage of development (Buhl and Buzsáki, 2005). It has been suggested that recurrent glutamatergic synaptic transmission (Dzhala and Staley, 2004) and pyramidal axoaxonic gap junctions (Traub et al.