title: The slow afterhyperpolarization: a target of β1-adrenergic signaling in hippocampus-dependent memory retrieval.
abstract: In rodents, adrenergic signaling by norepinephrine (NE) in the hippocampus is required for the retrieval of intermediate-term memory. NE promotes retrieval via the stimulation of β1-adrenergic receptors, the production of cAMP, and the activation of both protein kinase A (PKA) and the exchange protein activated by cAMP. However, a final effector for this signaling pathway has not been identified. Among the many targets of adrenergic signaling in the hippocampus, the slow afterhyperpolarization (sAHP) is an appealing candidate because its reduction by β1 signaling enhances excitatory neurotransmission. Here we report that reducing the sAHP is critical for the facilitation of retrieval by NE. Direct blockers of the sAHP, as well as blockers of the L-type voltage-dependent calcium influx that activates the sAHP, rescue retrieval in mutant mice lacking either NE or the β1 receptor. Complementary to this, a facilitator of L-type calcium influx impairs retrieval in wild-type mice. In addition, we examined the role of NE in the learning-related reduction of the sAHP observed ex vivo in hippocampal slices. We find that this reduction in the sAHP depends on the induction of persistent PKA activity specifically in conditioned slices. Interestingly, this persistent PKA activity is induced by NE/β1 signaling during slice preparation rather than during learning. These observations suggest that the reduction in the sAHP may not be present autonomously in vivo, but is likely induced by neuromodulatory input, which is consistent with the idea that NE is required in vivo for reduction of the sAHP during memory retrieval.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Ouyang
authors.forename: C Robin
authors.initials: CR
authors.lastname: Ganellin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003214:Conditioning, Classical / Q000502:physiology; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014700:Verapamil / Q000494:pharmacology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; C549620:3-(triphenylmethylaminomethyl)pyridine; D000873:Anthracenes; D001596:Benzylamines; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D018342:Receptors, Adrenergic, beta-1; C411671:TRAM 34; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D004299:Dopamine beta-Hydroxylase; D002118:Calcium; D009638:Norepinephrine