VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction
Abstract Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We fou...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53891-1 |
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| author | Harris E. Blankenship Kelsey A. Carter Kevin D. Pham Nina T. Cassidy Andrea N. Markiewicz Michael I. Thellmann Amanda L. Sharpe Willard M. Freeman Michael J. Beckstead |
| author_facet | Harris E. Blankenship Kelsey A. Carter Kevin D. Pham Nina T. Cassidy Andrea N. Markiewicz Michael I. Thellmann Amanda L. Sharpe Willard M. Freeman Michael J. Beckstead |
| author_sort | Harris E. Blankenship |
| collection | DOAJ |
| description | Abstract Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies. |
| format | Article |
| id | doaj-art-dd82a031eca54bdd80aba860fe826dbc |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dd82a031eca54bdd80aba860fe826dbc2025-08-20T02:13:28ZengNature PortfolioNature Communications2041-17232024-11-0115112010.1038/s41467-024-53891-1VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunctionHarris E. Blankenship0Kelsey A. Carter1Kevin D. Pham2Nina T. Cassidy3Andrea N. Markiewicz4Michael I. Thellmann5Amanda L. Sharpe6Willard M. Freeman7Michael J. Beckstead8Aging and Metabolism Research Program, Oklahoma Medical Research FoundationAging and Metabolism Research Program, Oklahoma Medical Research FoundationGenes and Human Disease Research Program, Oklahoma Medical Research FoundationAging and Metabolism Research Program, Oklahoma Medical Research FoundationAging and Metabolism Research Program, Oklahoma Medical Research FoundationAging and Metabolism Research Program, Oklahoma Medical Research FoundationDepartment of Pharmaceutical Sciences, University of Oklahoma Health Sciences CenterGenes and Human Disease Research Program, Oklahoma Medical Research FoundationAging and Metabolism Research Program, Oklahoma Medical Research FoundationAbstract Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies.https://doi.org/10.1038/s41467-024-53891-1 |
| spellingShingle | Harris E. Blankenship Kelsey A. Carter Kevin D. Pham Nina T. Cassidy Andrea N. Markiewicz Michael I. Thellmann Amanda L. Sharpe Willard M. Freeman Michael J. Beckstead VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction Nature Communications |
| title | VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction |
| title_full | VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction |
| title_fullStr | VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction |
| title_full_unstemmed | VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction |
| title_short | VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction |
| title_sort | vta dopamine neurons are hyperexcitable in 3xtg ad mice due to casein kinase 2 dependent sk channel dysfunction |
| url | https://doi.org/10.1038/s41467-024-53891-1 |
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