Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning

The role of neurotrophic factors as endogenous survival proteins for brain neurons remains contentious. In the cerebellum, the signals controlling survival of molecular layer interneurons (MLIs) are unknown, and direct evidence for the requirement of a full complement of MLIs for normal cerebellar function and motor learning has been lacking. Here, we show that Purkinje cells (PCs), the target of MLIs, express the neurotrophic factor GDNF during MLI development and survival of MLIs depends on GDNF receptors GFRα1 and RET. Conditional mutant mice lacking either receptor lose a quarter of their MLIs, resulting in compromised synaptic inhibition of PCs, increased PC firing frequency, and abnormal acquisition of eyeblink conditioning and vestibulo-ocular reflex performance, but not overall motor activity or coordination. These results identify an endogenous survival mechanism for MLIs and reveal the unexpected vulnerability and selective requirement of MLIs in the control of cerebellar-dependent motor learning. [Display omitted] •The signals controlling survival of molecular layer interneurons (MLIs) are unclear•Whether MLIs are involved in normal cerebellar function was unclear•Purkinje cells express GDNF, and survival of MLIs depends on GDNF receptors GFRα1 and RET•Requirement of MLIs for cerebellar-dependent motor learning Sergaki et al. find that conditional mutant mice lacking GDNF receptor GFRα1 or RET lose a quarter of their cerebellar molecular layer interneurons (MLIs), resulting in compromised motor learning but not overall motor coordination. These results identify an endogenous survival mechanism for MLIs and reveal their unexpected vulnerability in the control of cerebellar-dependent motor learning