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Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits

Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (Chat(CRE)Cul3(F/+)) recapitulated ASD-like social and sensory gating...

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Autores principales: Rapanelli, Maximiliano, Wang, Wei, Hurley, Edward, Feltri, Maria Laura, Pittenger, Christopher, Frick, Luciana Romina, Yan, Zhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873627/
https://www.ncbi.nlm.nih.gov/pubmed/36693858
http://dx.doi.org/10.1038/s41398-023-02306-8
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author Rapanelli, Maximiliano
Wang, Wei
Hurley, Edward
Feltri, Maria Laura
Pittenger, Christopher
Frick, Luciana Romina
Yan, Zhen
author_facet Rapanelli, Maximiliano
Wang, Wei
Hurley, Edward
Feltri, Maria Laura
Pittenger, Christopher
Frick, Luciana Romina
Yan, Zhen
author_sort Rapanelli, Maximiliano
collection PubMed
description Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (Chat(CRE)Cul3(F/+)) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in Chat(CRE)Cul3(F/+) mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC.
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spelling pubmed-98736272023-01-26 Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits Rapanelli, Maximiliano Wang, Wei Hurley, Edward Feltri, Maria Laura Pittenger, Christopher Frick, Luciana Romina Yan, Zhen Transl Psychiatry Article Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (Chat(CRE)Cul3(F/+)) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in Chat(CRE)Cul3(F/+) mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC. Nature Publishing Group UK 2023-01-24 /pmc/articles/PMC9873627/ /pubmed/36693858 http://dx.doi.org/10.1038/s41398-023-02306-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Rapanelli, Maximiliano
Wang, Wei
Hurley, Edward
Feltri, Maria Laura
Pittenger, Christopher
Frick, Luciana Romina
Yan, Zhen
Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
title Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
title_full Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
title_fullStr Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
title_full_unstemmed Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
title_short Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
title_sort cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with cul3 deficiency: role of prefrontal cortex projections in cognitive deficits
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873627/
https://www.ncbi.nlm.nih.gov/pubmed/36693858
http://dx.doi.org/10.1038/s41398-023-02306-8
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