VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction.

Autor:	Blankenship HE; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation.; Department of Physiology, University of Oklahoma Health Sciences Center., Carter KA; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation., Cassidy NT; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation.; Genes and Human Disease Research Program, Oklahoma Medical Research Foundation., Markiewicz AN; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation., Thellmann MI; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation., Sharpe AL; Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center., Freeman WM; Genes and Human Disease Research Program, Oklahoma Medical Research Foundation.; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA., Beckstead MJ; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation.; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 17. Date of Electronic Publication: 2023 Nov 17.
DOI:	10.1101/2023.11.16.567486
Abstrakt:	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.
Databáze:	MEDLINE
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