title: Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation.
abstract: Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define which cholinergic-dependent behaviors could be improved pharmacologically. Here we investigate the contributions of forebrain ACh on hippocampal synaptic plasticity and cognitive behavior by selective elimination of the vesicular ACh transporter, which interferes with synaptic storage and release of ACh. We show that elimination of vesicular ACh transporter in the hippocampus results in deficits in long-term potentiation and causes selective deficits in spatial memory. Moreover, decreased cholinergic tone in the forebrain is linked to hyperactivity, without changes in anxiety or depression-related behavior. These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy.
authors.affiliation: Molecular Brain Research Group, Robarts Research Institute, and Department of Anatomy and Cell Biology and Physiology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 5K8.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Martyn
authors.forename: Xavier
authors.initials: X
authors.lastname: De Jaeger
authors.forename: Ana C
authors.initials: AC
authors.lastname: Magalhães
authors.forename: Rohit
authors.initials: R
authors.lastname: Kesarwani
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Gonçalves
authors.forename: Sanda
authors.initials: S
authors.lastname: Raulic
authors.forename: Monica S
authors.initials: MS
authors.lastname: Guzman
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.forename: Ivan
authors.initials: I
authors.lastname: Izquierdo
authors.forename: John F
authors.initials: JF
authors.lastname: Macdonald
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D007858:Learning; D017774:Long-Term Potentiation; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D016133:Polymerase Chain Reaction; D016548:Prosencephalon / Q000378:metabolism*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: D050494:Vesicular Acetylcholine Transport Proteins