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Cover ArticleResearch Articles, Development/Plasticity/Repair

The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors

Juan P. Zanin, Jessica L. Verpeut, Ying Li, Michael W. Shiflett, Samuel S.-H. Wang, Viji Santhakumar and Wilma J. Friedman
Journal of Neuroscience 13 November 2019, 39 (46) 9119-9129; DOI: https://doi.org/10.1523/JNEUROSCI.0990-19.2019
Juan P. Zanin
1Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102,
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Jessica L. Verpeut
2Princeton Neuroscience Institute, Princeton, New Jersey 08544,
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Ying Li
3Department of Physiology, Pharmacology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey 07103,
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Michael W. Shiflett
4Department of Psychology, Rutgers University, Newark, New Jersey 07102, and
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Samuel S.-H. Wang
2Princeton Neuroscience Institute, Princeton, New Jersey 08544,
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Viji Santhakumar
3Department of Physiology, Pharmacology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey 07103, 5Department of Molecular, Cell and Systems Biology, University of California at Riverside, Riverside, California 92521
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Wilma J. Friedman
1Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102,
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Abstract

Development of brain circuitry requires precise regulation and timing of proliferation and differentiation of neural progenitor cells. The p75 neurotrophin receptor (p75NTR) is highly expressed in the proliferating granule cell precursors (GCPs) during development of the cerebellum. In a previous paper, we showed that proNT3 promoted GCP cell cycle exit via p75NTR. Here we used genetically modified rats and mice of both sexes to show that p75NTR regulates the duration of the GCP cell cycle, requiring activation of RhoA. Rats and mice lacking p75NTR have dysregulated GCP proliferation, with deleterious effects on cerebellar circuit development and behavioral consequences persisting into adulthood. In the absence of p75NTR, the GCP cell cycle is accelerated, leading to delayed cell cycle exit, prolonged GCP proliferation, increased glutamatergic input to Purkinje cells, and a deficit in delay eyeblink conditioning, a cerebellum-dependent form of learning. These results demonstrate the necessity of appropriate developmental timing of the cell cycle for establishment of proper connectivity and associated behavior.

SIGNIFICANCE STATEMENT The cerebellum has been shown to be involved in numerous behaviors in addition to its classic association with motor function. Cerebellar function is disrupted in a variety of psychiatric disorders, including those on the autism spectrum. Here we show that the p75 neurotrophin receptor, which is abundantly expressed in the proliferating cerebellar granule cell progenitors, regulates the cell cycle of these progenitors. In the absence of this receptor, the cell cycle is dysregulated, leading to excessive progenitor proliferation, which alters the balance of inputs to Purkinje cells, disrupting the circuitry and leading to functional deficits that persist into adulthood.

  • cerebellum
  • eyeblink conditioning
  • p75NTR
  • proliferation
  • RhoA
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The Journal of Neuroscience: 39 (46)
Journal of Neuroscience
Vol. 39, Issue 46
13 Nov 2019
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The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors
Juan P. Zanin, Jessica L. Verpeut, Ying Li, Michael W. Shiflett, Samuel S.-H. Wang, Viji Santhakumar, Wilma J. Friedman
Journal of Neuroscience 13 November 2019, 39 (46) 9119-9129; DOI: 10.1523/JNEUROSCI.0990-19.2019

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The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors
Juan P. Zanin, Jessica L. Verpeut, Ying Li, Michael W. Shiflett, Samuel S.-H. Wang, Viji Santhakumar, Wilma J. Friedman
Journal of Neuroscience 13 November 2019, 39 (46) 9119-9129; DOI: 10.1523/JNEUROSCI.0990-19.2019
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Keywords

  • cerebellum
  • eyeblink conditioning
  • p75NTR
  • proliferation
  • RhoA

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