title: Norepinephrine enhances a discrete form of long-term depression during fear memory storage.
abstract: Amygdala excitatory synaptic strengthening is thought to contribute to both conditioned fear and anxiety. Thus, one basis for behavioral flexibility could allow these pathways to be weakened and corresponding emotion to be attenuated. However, synaptic depression within the context of amygdala-dependent behavior remains poorly understood. Previous work identified lateral amygdala (LA) calcium-permeable AMPA receptors (CP-AMPARs) as a key target for synaptic removal in long-term depression (LTD) and persistent fear attenuation. Here we demonstrate that LA neurons express two equally potent forms of LTD with contrasting requirements for protein kinase and phosphatase activity and differential impact on CP-AMPAR trafficking. Selective removal of CP-AMPARs from synapses is contingent on group 1 metabotropic glutamate receptor (mGluR1) and PKC signaling, in contrast to an alternate LTD pathway that nonselectively removes AMPARs and requires calcineurin (PP2b). Intriguingly, the balance between these forms of LTD is shifted by posttraining activation of β-adrenergic receptors in fear conditioned mice, resulting in selective augmentation of mGluR-dependent depression. These results highlight the complexity of core mechanisms in LTD and suggest that norepinephrine exposure mediates a form of synaptic metaplasticity that recalibrates fear memory processing.
authors.affiliation: The Fishberg Department of Neuroscience and the Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. roger.clem@mssm.edu
authors.forename: Roger L
authors.initials: RL
authors.lastname: Clem
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D011433:Propranolol; D011493:Protein Kinase C; D019703:Calcineurin; D009638:Norepinephrine