The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors
| العنوان: | The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors |
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| المؤلفون: | Jessica L. Verpeut, Ying Li, Wilma J. Friedman, Samuel S.-H. Wang, Michael W. Shiflett, Juan P. Zanin, Viji Santhakumar |
| المصدر: | J Neurosci The Journal of neuroscience : the official journal of the Society for Neuroscience, vol 39, iss 46 |
| بيانات النشر: | Society for Neuroscience, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cerebellum, RHOA, Medical and Health Sciences, Transgenic, Mice, Purkinje Cells, 0302 clinical medicine, Neural Stem Cells, Receptors, Nerve Growth Factor, Research Articles, Neurons, biology, Growth Factor, General Neuroscience, Cell Cycle, Cell cycle, Neural stem cell, Cell biology, Mental Health, medicine.anatomical_structure, Eyeblink conditioning, Neurological, Stem Cell Research - Nonembryonic - Non-Human, Female, Rats, Transgenic, cerebellum, proliferation, 1.1 Normal biological development and functioning, Dendritic Spines, Mice, Transgenic, Nerve Tissue Proteins, Receptors, Nerve Growth Factor, eyeblink conditioning, Basic Behavioral and Social Science, p75NTR, 03 medical and health sciences, Underpinning research, Behavioral and Social Science, medicine, Animals, Receptors, Growth Factor, Progenitor cell, Cell Proliferation, Progenitor, Neurology & Neurosurgery, Psychology and Cognitive Sciences, Neurosciences, Excitatory Postsynaptic Potentials, RhoA, Stem Cell Research, Granule cell, Rats, Brain Disorders, 030104 developmental biology, biology.protein, 030217 neurology & neurosurgery |
| الوصف: | 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 STATEMENTThe 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1529-2401 0270-6474 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc358bf17cb6620d8cc1d1d61c56bfd6 https://doi.org/10.1523/jneurosci.0990-19.2019 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bc358bf17cb6620d8cc1d1d61c56bfd6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15292401 02706474 |
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