Evidence For Thalamic Participation In Seizures

(A) Spontaneous

Control

(A) Spontaneous

Control

-69 mV IPSPs

-69 mV IPSPs

Bicuculline

Action potential

Bicuculline and baclofen -70 mV

Wash

2s figure 13.2 Bicuculline-induced 3Hz oscillation in thalamic slices. (A) Control spindle sequence (~10Hz) started spontaneously by an IPSP (arrow). (B) Slow oscillation (~3 Hz) following block of GABAa receptors by bicuculline. (C) Suppression of the slow oscillation in the presence of the GABAb antagonist baclofen. (D) Recovery after wash. Modified from von Krosigk et al. (1993).

GABAb receptors leads to the suppression of spike-and-wave discharges (Liu et al., 1992), which is another indication for a critical role of the thalamus.

The two main thalamic cell types involved in generating oscillations are the thalamocortical (TC) cells, also called relay cells, and the inhibitory neurons of the thalamic reticular (RE) nucleus. In some area of the thalamus and in some species, RE cells provide the sole source of inhibition to relay cells. The connections from RE to TC cells contain both GABAa and GABAb receptors, and there is evidence that GABAb receptors are critical to generate hypersynchronized oscillations. In particular, clonazepam, a known anti-absence drug (GABAa antagonist), was shown indirectly to diminish GABAb-mediated inhibitory postsynaptic potentials (IPSPs) in TC cells, reducing their tendency to burst in synchrony (Huguenard and Prince, 1994a; Gibbs et al., 1996). The action of clonazepam appears to reinforce GABAa receptors within the RE nucleus (Huguenard and Prince, 1994a; Hosford et al., 1997). Indeed, there is a diminished frequency of seizures following reinforcement of GABAa receptors in the RE nucleus (Liu et al., 1991).

One of the strongest evidences for the involvement of the thalamus was that in ferret thalamic slices, spindle oscillations can be transformed into slower and more synchronized oscillations at ~3 Hz following blockade of GABAa receptors (Figure 13.2; von Krosigk et al., 1993). This behavior is similar to the transformation of spindles to spike-and-wave discharges in cats following the systemic administration of penicillin, which acts as a weak GABAa receptor antagonist (Kostopoulos et al., 1981a, 1981b). Moreover, like spike-and-wave seizures in rats, the ~3Hz paroxysmal oscillations in thalamic slices are suppressed by GABAb receptor antagonists (Figure 13.2; von Krosigk et al., 1993).

Taken together, these experiments suggest that thalamic neurons are actively involved in the genesis of spike-and-wave seizures and that both GABAa and GABAb receptors play a critical role. It is important to note, however, that although such results clearly suggest that the thalamus is important in seizure generation, there is also considerable evidence that the cortex plays a primary role. The role of the cortex will be developed in the next section, while we exclusively focus on thalamic mechanisms in the present section.

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