title: Prolonged ampakine exposure prunes dendritic spines and increases presynaptic release probability for enhanced long-term potentiation in the hippocampus.
abstract: CX 546, an allosteric positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPARs), belongs to a drug class called ampakines. These compounds have been shown to enhance long-term potentiation (LTP), a cellular model of learning and memory, and improve animal learning task performance, and have augmented cognition in neurodegenerative patients. However, the chronic effect of CX546 on synaptic structures has not been examined. The structure and integrity of dendritic spines are thought to play a role in learning and memory, and their abnormalities have been implicated in cognitive disorders. In addition, their structural plasticity has been shown to be important for cognitive function, such that dendritic spine remodeling has been proposed as the morphological correlate for LTP. Here, we tested the effect of CX546 on dendritic spine remodeling following long-term treatment. We found that, with prolonged CX546 treatment, organotypic hippocampal slice cultures showed a significant reduction in CA3-CA1 excitatory synapse and spine density. Electrophysiological approaches revealed that the CA3-CA1 circuitry compensates for this synapse loss by increasing synaptic efficacy through enhancement of presynaptic release probability. CX546-treated slices showed prolonged and enhanced potentiation upon LTP induction. Furthermore, structural plasticity, namely spine head enlargement, was also more pronounced after CX546 treatment. Our results suggest a concordance of functional and structural changes that is enhanced with prolonged CX546 exposure. Thus, the improved cognitive ability of patients receiving ampakine treatment may result from the priming of synapses through increases in the structural plasticity and functional reliability of hippocampal synapses.
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, Bellini Life Science Complex, Room 167, 3649 Promenade Sir-William-Osler, Montreal, QC, H3G 0B1, Canada.
authors.forename: Philip K-Y
authors.initials: PK
authors.lastname: Chang
authors.forename: George A
authors.initials: GA
authors.lastname: Prenosil
authors.forename: David
authors.initials: D
authors.lastname: Verbich
authors.forename: Raminder
authors.initials: R
authors.lastname: Gill
authors.forename: R Anne
authors.initials: RA
authors.lastname: McKinney
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects* / Q000502:physiology; D004146:Dioxanes / Q000494:pharmacology*; D004149:Dioxoles; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D004146:Dioxanes; D004149:Dioxoles; D018683:Excitatory Amino Acid Agents; D010880:Piperidines; D018091:Receptors, AMPA
keywords: CX546; LTP; organotypic hippocampal slices; synaptic plasticity; synaptic transmission