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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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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. |
format | Online Article Text |
id | pubmed-8549305 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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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