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Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK
Author(s) -
Maity Sabyasachi,
Chandanathil Merin,
Millis Richard M.,
Connor Steven A.
Publication year - 2020
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.14735
Subject(s) - long term potentiation , synaptic plasticity , norepinephrine , neuroscience , neurotransmission , chemistry , long term depression , biology , ampa receptor , receptor , nmda receptor , dopamine , biochemistry
Abstract Neuromodulators regulate higher‐order cognitive processes including learning and memory through modulation of synaptic transmission and plasticity. Norepinephrine is a neuromodulator that is secreted throughout the brain in response to novelty or increased arousal, which alters neural circuits by increasing the modifiability of CNS synapses. Norepinephrine activates metabotropic receptors, initiating complex intracellular signalling cascades that can promote enduring changes in synaptic strength including long‐term potentiation (LTP). In particular, activation of beta‐adrenergic receptors (β‐ARs) by norepinephrine enhances LTP through downstream engagement of signalling cascades which upregulate protein synthesis at synapses. Here, we sought to determine the select signalling pathways recruited by norepinephrine to promote homosynaptic LTP at hippocampal synapses in mice. Application of norepinephrine initiated a long‐lasting form of homosynaptic LTP that requires protein synthesis. Norepinephrine‐mediated enhancement of LTP was reduced by inhibition of mammalian target of rapamycin and exchange protein directly activated by cAMP (Epac) but not cAMP‐dependent protein kinase A, suggesting that the endogenous β‐AR ligand norepinephrine may preferentially recruit Epac signalling to promote enduring changes in synaptic strength. These findings advance our understanding of the mechanisms through which norepinephrine regulates synaptic plasticity associated with formation of new memories.

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