Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice

M. H. Bazalakova, J. Wright, E. J. Schneble, Michael Mcdonald, C. J. Heilman, A. I. Levey, R. D. Blakely

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (-/-) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/- mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/- mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/- mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity.

Original languageEnglish (US)
Pages (from-to)411-424
Number of pages14
JournalGenes, Brain and Behavior
Volume6
Issue number5
DOIs
StatePublished - Jul 1 2007

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Cholinergic Receptors
Homeostasis
Choline
Hemicholinium 3
Cholinergic Agents
Acetylcholine
Muscarinic Receptors
choline transporter
Cholinergic Neurons
Muscarinic Antagonists
Scopolamine Hydrobromide
Brain
Anxiety
Parturition
Pharmacology
Phenotype
Light
Water

All Science Journal Classification (ASJC) codes

  • Genetics
  • Neurology
  • Behavioral Neuroscience

Cite this

Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. / Bazalakova, M. H.; Wright, J.; Schneble, E. J.; Mcdonald, Michael; Heilman, C. J.; Levey, A. I.; Blakely, R. D.

In: Genes, Brain and Behavior, Vol. 6, No. 5, 01.07.2007, p. 411-424.

Research output: Contribution to journalArticle

Bazalakova, M. H. ; Wright, J. ; Schneble, E. J. ; Mcdonald, Michael ; Heilman, C. J. ; Levey, A. I. ; Blakely, R. D. / Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. In: Genes, Brain and Behavior. 2007 ; Vol. 6, No. 5. pp. 411-424.
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