Electrical activity in the forebrain is characterized by various patterns of synchronized oscillations during slow wave sleep. One prototypical example of synchronized oscillations during slow wave sleep is spindle waves, which appear as 6-12 Hz oscillations that wax and wane over a 1-4 second period in the electroencephalogram (EEG). In some cases of generalized epilepsy there is a direct relationship between the cellular mechanisms of generation of normal activity, such as spindle waves, and seizure activity, such as absence seizures. Our understanding of these normal and abnormal synchronized oscillations in the forebrain have been restricted due to technical limitations. However, we have recently developed an in vitro slice preparation (slices of the ferret dorsal lateral geniculate nucleus; LGNd) that spontaneously generates spindle waves and absence-seizure like events. Using the advantages of in vitro preparations, we can detail the precise cellular mechanisms of generation of this normal and abnormal activity. Of particular importance are the mechanisms by which the normal pattern of activity transforms into the absence seizure-like pattern, as well as the mechanisms by which both of these types of activity end. Based upon data collected so far, we have proposed that both oscillations are generated through an interaction between the GABAergic neurons of the perigeniculate nucleus and the thalamic relay cells and that the transition between the normal spindle wave generation and the absence seizure-like oscillation is due to a dramatic increase in firing of the perigeniculate GABAergic neurons resulting from disinhibition when GABAA receptors are blocked. This increase in activity in perigeniculate neurons is proposed to result in a large increase in the activation of GABAB receptors on thalamic relay cells, which is essential for the generation of the absence-seizure like network oscillation. In addition, we have obtained evidence that both spindle waves and the seizure-like oscillations naturally stop and exhibit a refractory period owing to the persistent activation of a particular ionic current, the hyperpolarization-activated cation current known as I- h. Our experiments will specifically test these hypotheses with intracellular and extracellular electrophysiological techniques. We will examine: the relationship between the pattern of action potentials in the GABAergic neurons and the postsynaptic activation of GABAA and GABAB receptors; possible changes in this synaptic connection that contribute to the refractory period; and finally the contribution of I-h to the refractory period. This data will significantly improve our understanding of both normal and abnormal activity generation in the forebrain and may indicate new pharmacological methods for the control of epileptic seizures.
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