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Cover ArticleResearch Articles, Cellular/Molecular

Dendritic Inhibition by Shh Signaling-Dependent Stellate Cell Pool Is Critical for Motor Learning

Wen Li, Lei Chen, Jonathan T. Fleming, Emily Brignola, Kirill Zavalin, Andre Lagrange, Tonia Rex, Shane A. Heiney, Gregory J. Wojaczynski, Javier F. Medina and Chin Chiang
Journal of Neuroscience 29 June 2022, 42 (26) 5130-5143; DOI: https://doi.org/10.1523/JNEUROSCI.2073-21.2022
Wen Li
1Departments of Cell and Developmental Biology and
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Lei Chen
1Departments of Cell and Developmental Biology and
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Jonathan T. Fleming
1Departments of Cell and Developmental Biology and
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Emily Brignola
1Departments of Cell and Developmental Biology and
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Kirill Zavalin
2Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232
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Andre Lagrange
2Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232
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Tonia Rex
3Department of Opthalmology & Visual Science, Vanderbilt Eye Institute, Nashville, Tennessee 37232
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Shane A. Heiney
4Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242
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Gregory J. Wojaczynski
5Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030
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Javier F. Medina
5Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030
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Chin Chiang
1Departments of Cell and Developmental Biology and
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Abstract

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and nonmotor functions. The molecular layer interneurons (MLIs), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons, which migrate from the prospective white matter to the ML of the cortex. However, little is known about 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 both BCs and SCs respond to the Sonic hedgehog (Shh) signal. Conditional abrogation of Shh signaling of either sex inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+ cells settle into their laminar positions in an inside-out sequence. 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 also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.

SIGNIFICANCE STATEMENT The cerebellar circuit that enables fine motor learning involves MLIs of BCs and SCs, which provide dendritic and somatic inhibitory synapses onto Purkinje cells. Little is known about how their identities and numbers are determined, nor are their specific contributions to motor learning well understood. We show that MLI subtypes are specified independent of Shh signaling and their birth orders but appear to occur in their terminal laminar positions according to the inside-out sequence. This finding challenges the current view that MLI subtypes are specified sequentially at the progenitor level. We also demonstrate that dendritic inhibition by Shh signaling-dependent SC pool is necessary for motor learning.

  • cerebellum
  • interneurons
  • motor learning
  • neurogenesis
  • Sonic hedgehog

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The Journal of Neuroscience: 42 (26)
Journal of Neuroscience
Vol. 42, Issue 26
29 Jun 2022
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Dendritic Inhibition by Shh Signaling-Dependent Stellate Cell Pool Is Critical for Motor Learning
Wen Li, Lei Chen, Jonathan T. Fleming, Emily Brignola, Kirill Zavalin, Andre Lagrange, Tonia Rex, Shane A. Heiney, Gregory J. Wojaczynski, Javier F. Medina, Chin Chiang
Journal of Neuroscience 29 June 2022, 42 (26) 5130-5143; DOI: 10.1523/JNEUROSCI.2073-21.2022

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Dendritic Inhibition by Shh Signaling-Dependent Stellate Cell Pool Is Critical for Motor Learning
Wen Li, Lei Chen, Jonathan T. Fleming, Emily Brignola, Kirill Zavalin, Andre Lagrange, Tonia Rex, Shane A. Heiney, Gregory J. Wojaczynski, Javier F. Medina, Chin Chiang
Journal of Neuroscience 29 June 2022, 42 (26) 5130-5143; DOI: 10.1523/JNEUROSCI.2073-21.2022
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Keywords

  • cerebellum
  • interneurons
  • motor learning
  • neurogenesis
  • Sonic hedgehog

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