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Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors

BACKGROUND: Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons r...

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Autores principales: Li, Xinyan, Chen, Wenting, Huang, Xian, Jing, Wei, Zhang, Tongmei, Yu, Quntao, Yu, Hongyan, Li, Hao, Tian, Qing, Ding, Yumei, Lu, Youming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549305/
https://www.ncbi.nlm.nih.gov/pubmed/34702328
http://dx.doi.org/10.1186/s13024-021-00494-9
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author Li, Xinyan
Chen, Wenting
Huang, Xian
Jing, Wei
Zhang, Tongmei
Yu, Quntao
Yu, Hongyan
Li, Hao
Tian, Qing
Ding, Yumei
Lu, Youming
author_facet Li, Xinyan
Chen, Wenting
Huang, Xian
Jing, Wei
Zhang, Tongmei
Yu, Quntao
Yu, Hongyan
Li, Hao
Tian, Qing
Ding, Yumei
Lu, Youming
author_sort Li, Xinyan
collection PubMed
description BACKGROUND: Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. METHODS: We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. RESULTS: We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. CONCLUSIONS: These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-021-00494-9.
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spelling pubmed-85493052021-10-27 Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors Li, Xinyan Chen, Wenting Huang, Xian Jing, Wei Zhang, Tongmei Yu, Quntao Yu, Hongyan Li, Hao Tian, Qing Ding, Yumei Lu, Youming Mol Neurodegener Research Article BACKGROUND: Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. METHODS: We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. RESULTS: We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. CONCLUSIONS: These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-021-00494-9. BioMed Central 2021-10-26 /pmc/articles/PMC8549305/ /pubmed/34702328 http://dx.doi.org/10.1186/s13024-021-00494-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Li, Xinyan
Chen, Wenting
Huang, Xian
Jing, Wei
Zhang, Tongmei
Yu, Quntao
Yu, Hongyan
Li, Hao
Tian, Qing
Ding, Yumei
Lu, Youming
Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
title Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
title_full Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
title_fullStr Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
title_full_unstemmed Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
title_short Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
title_sort synaptic dysfunction of aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549305/
https://www.ncbi.nlm.nih.gov/pubmed/34702328
http://dx.doi.org/10.1186/s13024-021-00494-9
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