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The Journal of Neuroscience, May 14, 2008, 28(20):5350-5358; doi:10.1523/JNEUROSCI.5058-06.2008

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Development/Plasticity/Repair
Coactivation of M₁ Muscarinic and 1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

Cary L. Scheiderer,^1 * Caroline C. Smith,^2 * Eve McCutchen,² Portia A. McCoy,¹ Erin E. Thacker,² Krystyna Kolasa,² Lynn E. Dobrunz,^1,2,3 and Lori L. McMahon^1,2,3

¹Departments of Neurobiology and ²Physiology and Biophysics, and ³Alzheimer's Disease Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

Correspondence should be addressed to Dr. Lori L. McMahon, University of Alabama at Birmingham, 1918 University Boulevard, MCLM 964, Birmingham, AL 35294-0005. Email: mcmahon{at}physiology.uab.edu

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 M₁ or adrenergic 1 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 Gq-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M₁ and 1 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 M₁ and 1 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 M₁ and 1 receptors could function to induce long-term changes in synaptic function important for cognition.

Key words: synaptic plasticity; acetylcholine; norepinephrine; U0126; carbachol; methoxamine

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Received Nov. 22, 2006; revised Feb. 28, 2008; accepted March 24, 2008.

Correspondence should be addressed to Dr. Lori L. McMahon, University of Alabama at Birmingham, 1918 University Boulevard, MCLM 964, Birmingham, AL 35294-0005. Email: mcmahon{at}physiology.uab.edu

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