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The Journal of Neuroscience, July 30, 2008, 28(31):7820-7827; doi:10.1523/JNEUROSCI.0223-08.2008

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Cellular/Molecular
PKM Maintains Late Long-Term Potentiation by N-Ethylmaleimide-Sensitive Factor/GluR2-Dependent Trafficking of Postsynaptic AMPA Receptors

Yudong Yao,^1 * Matthew Taylor Kelly,^1 * Sreedharan Sajikumar,² Peter Serrano,¹ Dezhi Tian,¹ Peter John Bergold,¹ Julietta Uta Frey,² and Todd Charlton Sacktor¹

¹The Robert F. Furchgott Center for Neural and Behavioral Science, Departments of Physiology, Pharmacology, and Neurology, State University of New York, Downstate Medical Center, Brooklyn, New York 11203, and ²Leibniz Institute for Neurobiology, Department of Neurophysiology, D-39118 Magdeburg, Germany

Correspondence should be addressed to Dr. Todd Charlton Sacktor, Department of Physiology and Pharmacology, Box 29, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203. Email: tsacktor{at}downstate.edu

Although the maintenance mechanism of late long-term potentiation (LTP) is critical for the storage of long-term memory, the expression mechanism of synaptic enhancement during late-LTP is unknown. The autonomously active protein kinase C isoform, protein kinase M (PKM), is a core molecule maintaining late-LTP. Here we show that PKM maintains late-LTP through persistent N-ethylmaleimide-sensitive factor (NSF)/glutamate receptor subunit 2 (GluR2)-dependent trafficking of AMPA receptors (AMPARs) to the synapse. Intracellular perfusion of PKM into CA1 pyramidal cells causes potentiation of postsynaptic AMPAR responses; this synaptic enhancement is mediated through NSF/GluR2 interactions but not vesicle-associated membrane protein-dependent exocytosis. PKM may act through NSF to release GluR2-containing receptors from a reserve pool held at extrasynaptic sites by protein interacting with C-kinase 1 (PICK1), because disrupting GluR2/PICK1 interactions mimic and occlude PKM-mediated AMPAR potentiation. During LTP maintenance, PKM directs AMPAR trafficking, as measured by NSF/GluR2-dependent increases of GluR2/3-containing receptors in synaptosomal fractions from tetanized slices. Blocking this trafficking mechanism reverses established late-LTP and persistent potentiation at synapses that have undergone synaptic tagging and capture. Thus, PKM maintains late-LTP by persistently modifying NSF/GluR2-dependent AMPAR trafficking to favor receptor insertion into postsynaptic sites.

Key words: PKM; PKC; NSF; GluR2; PICK1; LTP

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Received Jan. 17, 2008; revised May 15, 2008; accepted June 11, 2008.

Correspondence should be addressed to Dr. Todd Charlton Sacktor, Department of Physiology and Pharmacology, Box 29, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203. Email: tsacktor{at}downstate.edu

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