Blocking GABAA neurotransmission in the interposed nuclei: effects on conditioned and unconditioned eyeblinks

The interposed nuclei (IN) of the intermediate cerebellum are critical components of the circuits that control associative learning of eyeblinks and other defensive reflexes in mammals. The IN, which represent the sole output of the intermediate cerebellum, receive massive GABAergic input from Purkinje cells of the cerebellar cortex and are thought to contribute to the acquisition and performance of classically conditioned eyeblinks. The specific role of deep cerebellar nuclei and the cerebellar cortex in eyeblink conditioning are not well understood. One group of studies reported that blocking GABA(A) neurotransmission in the IN altered the time profile of conditioned responses (CRs), suggesting that the main function of the cerebellar cortex is to shape the timing of CRs. Other studies reported that blocking GABA(A) neurotransmission in the IN abolished CRs, indicating a more fundamental involvement of the cerebellar cortex in CR generation. When examining this controversy, we hypothesized that the behavioral effect of GABA(A) blockers could be dose-dependent. The IN of classically conditioned rabbits were injected with high and low doses of picrotoxin and gabazine. Both GABA(A) blockers produced tonic eyelid closure. A high dose of both drugs abolished CRs, whereas a less complete block of GABA(A)-mediated inputs with substantially smaller drug doses shortened CR latencies. In addition, low doses of picrotoxin facilitated the expression of unconditioned eyeblinks evoked by trigeminal stimulation. These results suggest that the intermediate cerebellum regulates both associative and non-associative components of the eyeblink reflex, and that behavioral effects of blocking Purkinje cell action on IN neurons are related to collective changes in cerebellar signals and in the excitability of extra-cerebellar eyeblink circuits.