Gross cerebellar structure is fine without LTD.

The cerebellum handles many motor coordination and reflexive behaviors, and learned adaptations of these behaviors are thought to require synaptic long-term depression (LTD). On page 295, Feil et al. identify a signaling pathway essential for LTD in cerebellar Purkinje cells but, surprisingly, this pathway is required only for a subset of motor reflex adaptations.

Using a conditional gene knock-out approach, the authors disrupted the expression of cGMP-dependent protein kinase type I (cGKI) in Purkinje cells, which normally express high levels of the kinase. The disruption virtually abolishes cerebellar LTD in the mutant mice, but the animals perform normally in several tests of motor coordination. However, adaptation of the vestibulo-ocular reflex of the mutant mice, which keeps images stable on the retina during head movements, is defective.

Feil et al. propose that cGKI links nitric oxide and cGMP signaling to phosphatase inhibition and AMPA receptor endocytosis, leading to synaptic LTD and motor learning. The behavioral results imply that LTD is only required for specific forms of motor learning, though, and not for general motor coordination. The authors are now trying to test their molecular model by conditionally deleting other components of the proposed signaling pathway. ▪