NeuroD2 controls inhibitory circuit formation in the molecular layer of the cerebellum

The cerebellar cortex is involved in the control of diverse motor and non-motor functions. Its principal circuit elements are the Purkinje cellsthat integrate incoming excitatory and local inhibitory inputs and provide the sole output of the cerebellar cortex. However, the transcriptional control of circuit assembly in the cerebellar cortex is not well understood. Here, we show that NeuroD2, a neuronal basic helix-loop-helix(bHLH) transcription factor, promotes the postnatal survival of both granule cellsand molecular layer interneurons (basket and stellate cells). However, while NeuroD2is not essential for the integration of surviving granule cellsinto the excitatory circuit, it is required for the terminal differentiation of basket cells. Axons of surviving NeuroD2-deficient basket cellsfollow irregular trajectories and their inhibitory terminals are virtually absent from Purkinje cellsin Neurod2mutants. As a result inhibitory, but not excitatory, input to Purkinje cellsis strongly reduced in the absence of NeuroD2. Together, we conclude that NeuroD2is necessary to instruct a terminal differentiation program in basket cellsthat regulates targeted axon growth and inhibitory synapse formation. An imbalance of excitation and inhibition in the cerebellar cortex affecting Purkinje celloutput may underlayimpaired adaptive motor learningobserved in Neurod2mutants.