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

Abstract

The cerebellar cortex is involved in the control of diverse motor and non-motor functions. Its principal circuit elements are the Purkinje cells that 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 cells and molecular layer interneurons (basket and stellate cells). However, while NeuroD2 is not essential for the integration of surviving granule cells into the excitatory circuit, it is required for the terminal differentiation of basket cells. Axons of surviving NeuroD2-deficient basket cells follow irregular trajectories and their inhibitory terminals are virtually absent from Purkinje cells in Neurod2 mutants. As a result inhibitory, but not excitatory, input to Purkinje cells is strongly reduced in the absence of NeuroD2. Together, we conclude that NeuroD2 is necessary to instruct a terminal differentiation program in basket cells that regulates targeted axon growth and inhibitory synapse formation. An imbalance of excitation and inhibition in the cerebellar cortex affecting Purkinje cell output may underlay impaired adaptive motor learning observed in Neurod2 mutants.

Origins, Development, and Compartmentation of the Granule Cells of the Cerebellum

“…Furthermore, misexpression of Neurod1 after the establishment of the EGL triggers radial migration and downregulates Atoh1 (Butts et al, 2014 ). The structurally-related protein NEUROD2 promotes the postnatal survival of both GCs and molecular layer interneurons (Pieper et al, 2019 ).…”

Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons

“…We detected significant enrichment for distinct families of TF motifs in DARs with increased (+A) or decreased (−A) accessibility over GIN differentiation. In +A DARs, these motifs suggest binding of several TFs with previously characterized roles in GIN fate specification, including the bHLH proteins NEUROD1, NEUROD2 and NKX6.2 ( 30 , 64 , 65 ). +A DARs were also enriched for binding motifs of TFs with roles outside of the nervous system, such as IRF3 (toll-like receptor signaling), HOXD3 (angiogenesis) and BCL11A (hemoglobin switching), thereby suggesting novel roles in GIN development and function ( 75 , 76 , 88 ).…”

Disruption of the transcription factorNEUROD2causes an autism syndrome via cell-autonomous defects in cortical projection neurons

“…Animals Mice (mus musculus) were group housed (2-5 mice/cage) with same-sex littermates on a 12 hour light-dark cycle with access to food and water ad libitum. NeuroD2 deficient mice were previously described 21,22 . Mice were bred and maintained on a mixed SVeV-129/C57BL/6J background.…”