title: The presynaptic choline transporter imposes limits on sustained cortical acetylcholine release and attention.
abstract: Functional variation in the gene encoding the presynaptic choline transporter (CHT) has been linked to attention-deficit/hyperactivity disorder. Here, we report that a heterozygous deletion in the CHT gene in mice (CHT(+/-)) limits the capacity of cholinergic neurons to sustain acetylcholine (ACh) release and attentional performance. Cortical microdialysis and amperometric methods revealed that, whereas wild-type and CHT(+/-) animals support equivalent basal ACh release and choline clearance, CHT(+/-) animals exhibit a significant inability to elevate extracellular ACh following basal forebrain stimulation, in parallel with a diminished choline clearance capacity following cessation of stimulation. Consistent with these findings, the density of CHTs in cortical synaptosomal plasma membrane-enriched fractions from unstimulated CHT(+/-) animals matched those observed in wild-type animals despite reductions in CHT levels in total extracts, achieved via a redistribution of CHT from vesicle pools. As a consequence, in CHT(+/-) animals, basal forebrain stimulation was unable to mobilize wild-type quantities of CHT to the plasma membrane. In behavioral studies, CHT(+/-) mice were impaired in performing a sustained attention task known to depend on cortical cholinergic activity. In wild-type mice, but not CHT(+/-) mice, attentional performance increased the density of CHTs in the synaptosomal membrane in the right frontal cortex. Basal CHT levels in vesicle-enriched membranes predicted the degree of CHT mobilization as well as individual variations in performance on the sustained attention task. Our findings demonstrate biochemical and physiological alterations that underlie cognitive impairments associated with genetically imposed reductions in choline uptake capacity.
authors: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, Pennsylvania 19122, USA.
authors: Vinay
authors: V
authors: Parikh
authors: Megan
authors: M
authors: St Peters
authors: Randy D
authors: RD
authors: Blakely
authors: Martin
authors: M
authors: Sarter
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001288:Attention / Q000502:physiology*; D005260:Female; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017729:Presynaptic Terminals / Q000378:metabolism*; D011897:Random Allocation
chemical_list: D026901:Membrane Transport Proteins; C065637:choline transporter; D000109:Acetylcholine
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