Spike-and-Wave Oscillations Based on the Properties of GABA_BReceptors

Abstract

Neocortical and thalamic neurons are involved in the genesis of generalized spike-and-wave (SW) epileptic seizures. The cellular mechanism of SW involves complex interactions between intrinsic neuronal firing properties and multiple types of synaptic receptors, but because of the complexity of these interactions the exact details of this mechanism are unclear. In this paper these types of interactions were investigated by using biophysical models of thalamic and cortical neurons. It is shown first that, because of the particular activation properties of GABA B receptor-mediated responses, simulated field potentials can display SW waveforms if cortical pyramidal cells and interneurons generate prolonged discharges in synchrony, without any other assumptions. Here the "spike" component coincided with the synchronous firing, whereas the "wave" component was generated mostly by slow GABA B -mediated K ϩ currents. Second, the model suggests that intact thalamic circuits can be forced into a ϳ3 Hz oscillatory mode by corticothalamic feedback. Here again, this property was attributable to the characteristics of GABA B -mediated inhibition. Third, in the thalamocortical system this property can lead to generalized ϳ3 Hz oscillations with SW field potentials. The oscillation consisted of a synchronous prolonged firing in all cell types, interleaved with a ϳ300 msec period of neuronal silence, similar to experimental observations during SW seizures. This model suggests that SW oscillations can arise from thalamocortical loops in which the corticothalamic feedback indirectly evokes GABA B -mediated inhibition in the thalamus. This mechanism is shown to be consistent with a number of different experimental models, and experiments are suggested to test its consistency.

Cortically-induced coherence of a thalamic-generated oscillation

“…8C, left). In network simulations, enhancing the excitability of RE cells had a marked effect on oscillation frequency, as analysed previously, 17 but there was no prominent effect on the simultaneity and spatiotemporal coherence of oscillations (Fig. 8C, right).…”

“…In this case, the disinhibited pyramidal cells fired strong discharges and entrained the network in a ϳ3 Hz oscillation, similar to the analysis of a previous model of spike-and-wave. 17 It is indeed known from experimental data that blocking GABA A receptors in cerebral cortex leads to spike-and-wave seizures at 2-3 Hz. 42a,43a Enhancing the excitability of thalamic cells was also investigated.…”

Cellular and network mechanisms of electrographic seizures

“…In computational models, the "wave" was similarly regarded as produced by GABA B -mediated IPSPs (Destexhe 1998). However, during the EEG "waves" associated with neuronal hyperpolarization, the input resistance increases relative to the "spike" component (Matsumoto et al 1969;Neckelmann et al 2000;Timofeev et al 2002b).…”

Generalized Epileptic Disorders: An Update

“…In these studies, the burst responses of thalamic neurons as well as the properties of GABA B receptor-activated conductances have been shown to be critical in generating spike-and-wave discharges (86). Recently, similar approaches have been used to establish why thalamocortical circuits generate spike-and-wave discharges with different intraburst frequencies (i.e., 3 Hz in humans vs. 5-10 Hz in rodents).…”