VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction
Year: 2024
Type: article
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). Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings shed light on a complex interplay between neuropsychiatric symptoms and subcortical circuits in AD, paving the way for novel treatment strategies.
Source: Nature Communications
Authors: 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
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: Oklahoma Center for Adult Stem Cell Research, U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, Presbyterian Health Foundation, Oklahoma Center for the Advancement of Science and Technology, Tobacco Settlement Endowment Trust, National Institutes of Health, National Institute on Aging
Awards: G1385259538, Sex divergence and cell specificity of age-related hippocampal DNA modifications, G1646224748, G1686357462, G2910519581, G3057718421, G4694532912, G4794739514, Ventral tegmental area involvement in Alzheimer's pathology, G5128062318, G692538568, G7034736342, G7513047283, G7853535758, Oklahoma Nathan Shock Center of Excellence in Basic Biology of Aging, G818202304, Effects of dietary restriction on age-related neurophysiological adaptations: frombehavior to single dopaminergic neurons, Multimodal ventral tegmental area decrements in a mouse Alzheimer's model, G9000038095, G9000079944, G9000120120, G9000194690, G9000226600, G936691758
OpenAlex ID: W4404187293