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ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors
Natural genetic variants of Neuregulin1 (NRG1) and its cognate receptor ErbB4 are associated with a risk for schizophrenia. Whereas most studies on NRG1-ErbB4 signaling have focused on GABAergic interneurons, ErbB4 is also expressed by midbrain dopaminergic neurons where it modulates extracellular d...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society for Neuroscience
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242816/ https://www.ncbi.nlm.nih.gov/pubmed/32354758 http://dx.doi.org/10.1523/ENEURO.0395-19.2020 |
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author | Skirzewski, Miguel Cronin, Marie E. Murphy, Ricardo Fobbs, Wambura Kravitz, Alexxai V. Buonanno, Andres |
author_facet | Skirzewski, Miguel Cronin, Marie E. Murphy, Ricardo Fobbs, Wambura Kravitz, Alexxai V. Buonanno, Andres |
author_sort | Skirzewski, Miguel |
collection | PubMed |
description | Natural genetic variants of Neuregulin1 (NRG1) and its cognate receptor ErbB4 are associated with a risk for schizophrenia. Whereas most studies on NRG1-ErbB4 signaling have focused on GABAergic interneurons, ErbB4 is also expressed by midbrain dopaminergic neurons where it modulates extracellular dopamine (DA) levels. Here, we report that extracellular steady-state levels of DA are reduced in the medial prefrontal cortex (mPFC; −65%), hippocampus (−53%) and nucleus accumbens (NAc; −35%), but are elevated in the dorsal striatum (+25%) of ErbB4 knock-out mice (ErbB4 KOs) relative to wild-type controls. This pattern of DA imbalance recapitulates the reported prefrontal cortical reduction and striatal increase of DA levels in schizophrenia patients. Next, we report on a battery of behavioral tasks used to evaluate locomotor, cognitive and motivational behaviors in ErbB4 KOs relative to controls. We found that ErbB4 KOs are hyperactive in a novel open field but not in their familiar home cage, are more sensitive to amphetamine, perform poorly in the T-maze and novel object recognition (NOR) tasks, exhibit reduced spatial learning and memory on the Barnes maze, and perform markedly worse in conditioned place preference (CPP) tasks when associating cued-reward palatable food with location. However, we found that the poor performance of ErbB4 KOs in CPP are likely due to deficits in spatial memory, instead of reward seeking, as ErbB4 KOs are more motivated to work for palatable food rewards. Our findings indicate that ErbB4 signaling affects tonic DA levels and modulates a wide array of behavioral deficits relevant to psychiatric disorders, including schizophrenia. |
format | Online Article Text |
id | pubmed-7242816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Society for Neuroscience |
record_format | MEDLINE/PubMed |
spelling | pubmed-72428162020-05-22 ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors Skirzewski, Miguel Cronin, Marie E. Murphy, Ricardo Fobbs, Wambura Kravitz, Alexxai V. Buonanno, Andres eNeuro Research Article: New Research Natural genetic variants of Neuregulin1 (NRG1) and its cognate receptor ErbB4 are associated with a risk for schizophrenia. Whereas most studies on NRG1-ErbB4 signaling have focused on GABAergic interneurons, ErbB4 is also expressed by midbrain dopaminergic neurons where it modulates extracellular dopamine (DA) levels. Here, we report that extracellular steady-state levels of DA are reduced in the medial prefrontal cortex (mPFC; −65%), hippocampus (−53%) and nucleus accumbens (NAc; −35%), but are elevated in the dorsal striatum (+25%) of ErbB4 knock-out mice (ErbB4 KOs) relative to wild-type controls. This pattern of DA imbalance recapitulates the reported prefrontal cortical reduction and striatal increase of DA levels in schizophrenia patients. Next, we report on a battery of behavioral tasks used to evaluate locomotor, cognitive and motivational behaviors in ErbB4 KOs relative to controls. We found that ErbB4 KOs are hyperactive in a novel open field but not in their familiar home cage, are more sensitive to amphetamine, perform poorly in the T-maze and novel object recognition (NOR) tasks, exhibit reduced spatial learning and memory on the Barnes maze, and perform markedly worse in conditioned place preference (CPP) tasks when associating cued-reward palatable food with location. However, we found that the poor performance of ErbB4 KOs in CPP are likely due to deficits in spatial memory, instead of reward seeking, as ErbB4 KOs are more motivated to work for palatable food rewards. Our findings indicate that ErbB4 signaling affects tonic DA levels and modulates a wide array of behavioral deficits relevant to psychiatric disorders, including schizophrenia. Society for Neuroscience 2020-05-21 /pmc/articles/PMC7242816/ /pubmed/32354758 http://dx.doi.org/10.1523/ENEURO.0395-19.2020 Text en Copyright © 2020 Skirzewski et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article: New Research Skirzewski, Miguel Cronin, Marie E. Murphy, Ricardo Fobbs, Wambura Kravitz, Alexxai V. Buonanno, Andres ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors |
title | ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors |
title_full | ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors |
title_fullStr | ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors |
title_full_unstemmed | ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors |
title_short | ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors |
title_sort | erbb4 null mice display altered mesocorticolimbic and nigrostriatal dopamine levels as well as deficits in cognitive and motivational behaviors |
topic | Research Article: New Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242816/ https://www.ncbi.nlm.nih.gov/pubmed/32354758 http://dx.doi.org/10.1523/ENEURO.0395-19.2020 |
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