Blocking glutamate-mediated inferior olivary signals abolishes expression of conditioned eyeblinks but does not prevent their acquisition.

The inferior olive (IO) is considered a crucial component of the eyeblink conditioning network. The cerebellar learning hypothesis proposes that the IO provides the cerebellum with a teaching signal that is required for the acquisition and maintenance of conditioned eyeblinks. Supporting this concept, previous experiments showed that lesions or inactivation of the IO blocked CR acquisition. However, these studies were not conclusive. The drawback of the methods used by those studies is that they not only blocked task-related signals, but also completely shut down the spontaneous activity within the IO, which affects the rest of the eyeblink circuits in a nonspecific manner. We hypothesized that more selective blocking of task-related IO signals could be achieved by using injections of glutamate antagonists, which reduce, but do not eliminate, the spontaneous activity in the IO. We expected that if glutamate-mediated IO signals are required for learning, then blocking these signals during training sessions should prevent conditioned response (CR) acquisition. To test this prediction, rabbits were trained to acquire conditioned eyeblinks to a mild vibrissal airpuff as the conditioned stimulus while injections of the glutamate antagonist γ-d-glutamylglycine were administered to the IO. Remarkably, even though this treatment suppressed CRs during training sessions, the postacquisition retention test revealed that CR acquisition had not been abolished. The ability to acquire CRs with IO unconditioned stimulus signals that were blocked or severely suppressed suggests that mechanisms responsible for CR acquisition are extremely resilient and probably less dependent on IO-task-related signals than previously thought.