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Cell Rep. 2017 Jun 6;19(10):1977-1986. doi: 10.1016/j.celrep.2017.05.030.

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

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Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden.
Division of Neurosciences, Pablo de Olavide University, Seville 41013, Spain.
Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden; Department of Physiology, National University of Singapore, Singapore 117597, Singapore; Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore. Electronic address:


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.


Purkinje cell; cerebellum; eyeblink conditioning; neuronal migration; synaptic inhibition; vestibulo-ocular reflex

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