Role of the fastigial nucleus in generalized seizures as demonstrated by GABA agonist microinjections

The cerebellum is electrically and metabolically active during seizures. Numerous studies have also shown that cerebellar electrical stimulation and lesions of the cerebellar cortex or nuclei influence seizure threshold, but there are significant contradictions, with different effects observed even in investigations using the same species and similar seizure types and experimental manipulations. Discrete intracerebral microinjection of neuroactive agents has been used to characterize the way in which other brain regions control seizures, but has not been applied to the cerebellar systems. This approach has advantages because effects are restricted to specific receptors and spare passing axons; experimental variables also can be simply specified and reproduced. We used this method to characterize the role of the cerebellar nuclei in seizures and to determine if observed effects could be reproduced with different agents at different doses. Effects of bilateral control microinjections in the fastigial (medial) cerebellar nucleus were compared with different doses of the GABAA agonist piperidine-4-sulfonic acid and the GABAB agonist (-)baclofen (Bf). Soon after injection, the animals were ataxic. After 4 min, seizures were induced by timed continuous intravenous (i.v.) bicuculline (BIC) infusion. Both GABA agonists produced significant reductions in myoclonic, clonic, and tonic seizure thresholds. Injections just dorsal or anterior to this nucleus and bilateral dentate (lateral) nucleus injections had little effect on seizures. These results demonstrate that the cerebellar system does control seizures, but does not provide support for the early concept that cerebellar stimulation and systemic phenytoin block seizures through inhibition of cerebellar nuclei secondary to Purkinje cell activation.