Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression.
Animals
Behavior, Animal
/ physiology
Cerebral Cortex
/ physiology
Corpus Striatum
/ metabolism
Forkhead Transcription Factors
/ metabolism
Gene Expression Regulation, Developmental
/ genetics
Mice
Mice, Knockout
Neurons
/ physiology
Receptors, Dopamine D1
/ metabolism
Repressor Proteins
/ metabolism
Reversal Learning
/ physiology
Foxp2
dopamine
prefrontal cortex
reversal learning
single-cell RNA-seq
Journal
Cerebral cortex (New York, N.Y. : 1991)
ISSN: 1460-2199
Titre abrégé: Cereb Cortex
Pays: United States
ID NLM: 9110718
Informations de publication
Date de publication:
14 03 2020
14 03 2020
Historique:
received:
14
05
2019
revised:
23
07
2019
accepted:
14
08
2019
pubmed:
12
11
2019
medline:
16
6
2021
entrez:
12
11
2019
Statut:
ppublish
Résumé
Genetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders (NDDs) involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper layer neurons and interneurons. Together, these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to NDDs.
Identifiants
pubmed: 31711176
pii: 5618751
doi: 10.1093/cercor/bhz209
pmc: PMC7132914
doi:
Substances chimiques
Drd1 protein, mouse
0
Forkhead Transcription Factors
0
Foxp2 protein, mouse
0
Receptors, Dopamine D1
0
Repressor Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1855-1870Subventions
Organisme : NIDCD NIH HHS
ID : R01 DC014702
Pays : United States
Organisme : NIDCD NIH HHS
ID : R21 DC016340
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001104
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH102603
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM109776
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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