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Dendritic GABAergic inhibition controlled by Shh signaling-dependent stellate cell pool is critical for motor learning

By Wen Li, Lei Chen, Jonathan T Fleming, Emily Y Brignola, Kirill Zavalin, Andre Lagrange, Tonia Rex, Shane A heiney, Gregory J Wojaczynski, Javier F Medina, Chin Chiang

Posted 15 Apr 2021
bioRxiv DOI: 10.1101/2021.04.15.439999

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and non-motor functions. The molecular layer interneurons (MLI), consisting of basket cells (BCs) and stellate cells (SCs), are generated sequentially from Pax2+ immature interneurons which migrate from the prospective white matter to the ML of the cortex. However, little is known as to how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well-understood. Here, we show that GABAergic progenitors fated to generate BCs and SCs transiently respond to the Shh signal. Conditional abrogation of Shh signaling reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes did not affect BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are generated resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of their birth order and occurs after Pax2+ cells settle into their final laminar positions. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.

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