title: Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex.
abstract: One of the key brain regions in cognitive processing and executive function is the prefrontal cortex (PFC), which receives cholinergic input from basal forebrain cholinergic neurons. We evaluated the contribution of synaptically released acetylcholine (ACh) to executive function by genetically targeting the vesicular acetylcholine transporter (VAChT) in the mouse forebrain. Executive function was assessed using a pairwise visual discrimination paradigm and the 5-choice serial reaction time task (5-CSRT). In the pairwise test, VAChT-deficient mice were able to learn, but were impaired in reversal learning, suggesting that these mice present cognitive inflexibility. Interestingly, VAChT-targeted mice took longer to reach criteria in the 5-CSRT. Although their performance was indistinguishable from that of control mice during low attentional demand, increased attentional demand revealed striking deficits in VAChT-deleted mice. Galantamine, a cholinesterase inhibitor used in Alzheimer's disease, significantly improved the performance of control mice, but not of VAChT-deficient mice on the 5-CSRT. In vivo magnetic resonance spectroscopy showed altered levels of two neurochemical markers of neuronal function, taurine and lactate, suggesting altered PFC metabolism in VAChT-deficient mice. The PFC of these mice displayed a drastic reduction in the splicing factor heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), whose cholinergic-mediated reduction was previously demonstrated in Alzheimer's disease. Consequently, several key hnRNPA2/B1 target transcripts involved in neuronal function present changes in alternative splicing in VAChT-deficient mice, including pyruvate kinase M, a key enzyme involved in lactate metabolism. We propose that VAChT-targeted mice can be used to model and to dissect the neurochemical basis of executive abnormalities.
authors.affiliation: Robarts Research Institute, Graduate Program in Neuroscience, Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, N6A 5K8, and Department of Biological Chemistry and The Edmond and Lily Safra Center of Brain Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kolisnyk
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Al-Onaizi
authors.forename: Pedro H F
authors.initials: PH
authors.lastname: Hirata
authors.forename: Monica S
authors.initials: MS
authors.lastname: Guzman
authors.forename: Simona
authors.initials: S
authors.lastname: Nikolova
authors.forename: Shahar
authors.initials: S
authors.lastname: Barbash
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.forename: Robert
authors.initials: R
authors.lastname: Bartha
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D056344:Executive Function / Q000502:physiology*; D005702:Galantamine / Q000494:pharmacology; D007294:Inositol / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010775:Photic Stimulation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D011597:Psychomotor Performance / Q000187:drug effects; D012326:RNA Splicing / Q000235:genetics*; D013654:Taurine / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D002800:Cholinesterase Inhibitors; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D005702:Galantamine; D013654:Taurine; D001224:Aspartic Acid; D019344:Lactic Acid; D007294:Inositol; C000179:N-acetylaspartate; D002794:Choline; D000109:Acetylcholine
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