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

TitleThe p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors.
Publication TypeJournal Article
Year of Publication2019
AuthorsZanin, JP, Verpeut, JL, Li, Y, Shiflett, MW, Wang, SS-H, Santhakumar, V, Friedman, WJ
JournalJ Neurosci
Volume39
Issue46
Pagination9119-9129
Date Published2019 11 13
ISSN1529-2401
KeywordsAnimals, Cell Cycle, Cell Proliferation, Cerebellum, Dendritic Spines, Excitatory Postsynaptic Potentials, Female, Male, Mice, Transgenic, Neural Stem Cells, Neurons, Purkinje Cells, Rats, Transgenic, Receptors, Nerve Growth Factor
Abstract

<p>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. 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.</p>

DOI10.1523/JNEUROSCI.0990-19.2019
Alternate JournalJ Neurosci
PubMed ID31582529
PubMed Central IDPMC6855675
Grant ListR56 NS094589 / NS / NINDS NIH HHS / United States
R01 MH115750 / MH / NIMH NIH HHS / United States
R01 NS069861 / NS / NINDS NIH HHS / United States
R01 NS045193 / NS / NINDS NIH HHS / United States
R01 NS097750 / NS / NINDS NIH HHS / United States