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Individual differences in stereotypy and neuron subtype translatome with TrkB deletion

Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanis...

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Autores principales: Engeln, Michel, Song, Yang, Chandra, Ramesh, La, Ashley, Fox, Megan E., Evans, Brianna, Turner, Makeda D., Thomas, Shavin, Francis, T. Chase, Hertzano, Ronna, Lobo, Mary Kay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480032/
https://www.ncbi.nlm.nih.gov/pubmed/32366954
http://dx.doi.org/10.1038/s41380-020-0746-0
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author Engeln, Michel
Song, Yang
Chandra, Ramesh
La, Ashley
Fox, Megan E.
Evans, Brianna
Turner, Makeda D.
Thomas, Shavin
Francis, T. Chase
Hertzano, Ronna
Lobo, Mary Kay
author_facet Engeln, Michel
Song, Yang
Chandra, Ramesh
La, Ashley
Fox, Megan E.
Evans, Brianna
Turner, Makeda D.
Thomas, Shavin
Francis, T. Chase
Hertzano, Ronna
Lobo, Mary Kay
author_sort Engeln, Michel
collection PubMed
description Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanisms leading to direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows repetitive rotations and head tics with juvenile onset. Here we demonstrate these behaviors may be associated with abnormal direct-pathway activity by reducing rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny neurons (D1-MSNs) in both juvenile and young adult mice. Taking advantage of phenotypical differences in animals with similar genotype, we then interrogated the D1-MSN specific translatome associated with repetitive behavior by using RNA-sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by multiplexed gene expression assessment revealed profound alterations in neuronal projection and synaptic structure related genes in stereotypy mice. Examination of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results uncover phenotype-specific molecular alterations in D1-MSNs that relate to morphological adaptations in mice displaying stereotypy behavior.
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spelling pubmed-84800322021-09-29 Individual differences in stereotypy and neuron subtype translatome with TrkB deletion Engeln, Michel Song, Yang Chandra, Ramesh La, Ashley Fox, Megan E. Evans, Brianna Turner, Makeda D. Thomas, Shavin Francis, T. Chase Hertzano, Ronna Lobo, Mary Kay Mol Psychiatry Article Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanisms leading to direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows repetitive rotations and head tics with juvenile onset. Here we demonstrate these behaviors may be associated with abnormal direct-pathway activity by reducing rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny neurons (D1-MSNs) in both juvenile and young adult mice. Taking advantage of phenotypical differences in animals with similar genotype, we then interrogated the D1-MSN specific translatome associated with repetitive behavior by using RNA-sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by multiplexed gene expression assessment revealed profound alterations in neuronal projection and synaptic structure related genes in stereotypy mice. Examination of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results uncover phenotype-specific molecular alterations in D1-MSNs that relate to morphological adaptations in mice displaying stereotypy behavior. 2020-05-04 2021-06 /pmc/articles/PMC8480032/ /pubmed/32366954 http://dx.doi.org/10.1038/s41380-020-0746-0 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Engeln, Michel
Song, Yang
Chandra, Ramesh
La, Ashley
Fox, Megan E.
Evans, Brianna
Turner, Makeda D.
Thomas, Shavin
Francis, T. Chase
Hertzano, Ronna
Lobo, Mary Kay
Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
title Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
title_full Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
title_fullStr Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
title_full_unstemmed Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
title_short Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
title_sort individual differences in stereotypy and neuron subtype translatome with trkb deletion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480032/
https://www.ncbi.nlm.nih.gov/pubmed/32366954
http://dx.doi.org/10.1038/s41380-020-0746-0
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