Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice.
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.
Bazalakova
M H
MH
Neuroscience Graduate Program, MSTP, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN 37242-8548, USA.
Wright
J
J
Schneble
E J
EJ
McDonald
M P
MP
Heilman
C J
CJ
Levey
A I
AI
Blakely
R D
RD
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology*; D006426:Hemicholinium 3 / Q000494:pharmacology; D006579:Heterozygote; D018782:Maze Learning / Q000502:physiology; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D045442:Rotarod Performance Test; D012601:Scopolamine / Q000494:pharmacology; D013037:Spatial Behavior / Q000502:physiology*
D018678:Cholinergic Agents; D026901:Membrane Transport Proteins; D011976:Receptors, Muscarinic; C065637:choline transporter; D006426:Hemicholinium 3; D012601:Scopolamine; D000109:Acetylcholine