title: Norepinephrine triggers metaplasticity of LTP by increasing translation of specific mRNAs.
abstract: Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (β)-adrenergic receptors (β-ARs). Previous studies demonstrated that a β-adrenergic receptor agonist, isoproterenol, can modify the threshold for long-term potentiation (LTP), a putative cellular mechanism for learning and memory, in a process known as "metaplasticity." Metaplasticity is the ability of synaptic plasticity to be modified by prior experience. We asked whether NE itself could engage metaplastic mechanisms in area CA1 of mouse hippocampal slices. Using extracellular field potential recording and stimulation, we show that application of NE (10 µM), which did not alter basal synaptic strength, enhances the future maintenance of LTP elicited by subthreshold, high-frequency stimulation (HFS: 1 × 100 Hz, 1 sec). HFS applied 30 min after NE washout induced long-lasting (>4 h) LTP, which was significantly extended in duration relative to HFS alone. This NE-induced metaplasticity required β1-AR activation, as coapplication of the β1-receptor antagonist CGP-20712A (1 µM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translation- and transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NE-induced metaplasticity. Thus, activation of β-ARs by NE primes synapses for future long-lasting plasticity on time scales extending beyond fast synaptic transmission; this may facilitate neural information processing and the subsequent formation of lasting memories.
authors.affiliation: Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Maity
authors.affiliation: Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: Rah
authors.affiliation: Department of Biochemistry, Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: Patrick Wild Centre and Centre for Integrative Biology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Christos G
authors.initials: CG
authors.lastname: Gkogkas
authors.affiliation: Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada Department of Psychiatry, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada Neuroscience and Mental Health Institute, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada peter.nguyen@ualberta.ca.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Nguyen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
chemical_list: D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D021122:Protein Subunits; D012333:RNA, Messenger; D018091:Receptors, AMPA; D011943:Receptors, Adrenergic, beta; C049763:CGP 20712A; D009638:Norepinephrine