VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction.
Harris E BlankenshipKelsey A CarterNina T CassidyAndrea N MarkiewiczMichael I ThellmannAmanda L SharpeWillard M FreemanMichael J BecksteadPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- spinal cord
- single cell
- mouse model
- protein kinase
- end stage renal disease
- high fat diet induced
- chronic kidney disease
- oxidative stress
- white matter
- type diabetes
- ejection fraction
- tyrosine kinase
- spinal cord injury
- peritoneal dialysis
- metabolic syndrome
- rna seq
- gene expression
- high resolution
- genome wide
- cognitive decline
- multiple sclerosis
- adipose tissue
- skeletal muscle
- wild type