title: Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: a model of cholinergic capacity limits.
abstract: Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/- mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/- mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/- mice. Additionally, CHT+/- mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4β2* nAChRs in the cortex of CHT+/- mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/- cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/- model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders.
authors: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI 48103.
authors: Giovanna
authors: G
authors: Paolone
authors: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI 48103.
authors: Caitlin S
authors: CS
authors: Mallory
authors: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI 48103.
authors: Ajeesh Koshy
authors: AK
authors: Cherian
authors: Neuroscience Discovery, AbbVie Inc., North Chicago, IL 60064.
authors: Thomas R
authors: TR
authors: Miller
authors: Departments of Pharmacology and Psychiatry, Vanderbilt University, Nashville, TN 37232-8548.
authors: Randy D
authors: RD
authors: Blakely
authors: Department of Psychology & Neuroscience Program, University of Michigan, Ann Arbor, MI 48103.
authors: Martin
authors: M
authors: Sarter
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000470:Alkaloids / Q000493:pharmacokinetics; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D001392:Azocines / Q000493:pharmacokinetics; D018680:Cholinergic Antagonists / Q000494:pharmacology; D003216:Conditioning, Operant; D005260:Female; D006801:Humans; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects; D011807:Quinolizines / Q000493:pharmacokinetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics; D000093843:Quinolizidine Alkaloids
chemical_list: D000109:Acetylcholine; D000470:Alkaloids; D001285:Atropine; D001392:Azocines; D018680:Cholinergic Antagonists; D008464:Mecamylamine; D026901:Membrane Transport Proteins; D011807:Quinolizines; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D014316:Tritium; C065637:choline transporter; C004712:cytisine; D000093843:Quinolizidine Alkaloids
keywords: Acetylcholine; Attention; Choline transporter; Microdialysis; Mouse; Nicotinic acetylcholine receptor
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