title: Coactivation of M(1) muscarinic and alpha1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 synapses in rat hippocampus.
abstract: Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M(1) or adrenergic alpha1 receptors induces activity- and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common Galphaq-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M(1) and alpha1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signal-regulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M(1) and alpha1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M(1) and alpha1 receptors could function to induce long-term changes in synaptic function important for cognition.
authors.affiliation: Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
authors.forename: Cary L
authors.initials: CL
authors.lastname: Scheiderer
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Smith
authors.forename: Eve
authors.initials: E
authors.lastname: McCutchen
authors.forename: Portia A
authors.initials: PA
authors.lastname: McCoy
authors.forename: Erin E
authors.initials: EE
authors.lastname: Thacker
authors.forename: Krystyna
authors.initials: K
authors.lastname: Kolasa
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Dobrunz
authors.forename: Lori L
authors.initials: LL
authors.lastname: McMahon
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D018340:Receptors, Adrenergic, alpha-1; D043562:Receptors, G-Protein-Coupled; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000109:Acetylcholine; D009638:Norepinephrine