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The Journal of Neuroscience, December 13, 2006, 26(50):12943-12955; doi:10.1523/JNEUROSCI.2561-06.2006
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Development/Plasticity/Repair
Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus
Shenfeng Qiu,1 Lisa F. Zhao,1 Kimberly M. Korwek,3 andEdwin J. Weeber1,2,4 1Departments of Molecular Physiology and Biophysics and 2Pharmacology, 3Neuroscience Graduate Program, and 4Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615
Correspondence should be addressed to Dr. Edwin J. Weeber, Department of Molecular Physiology and Biophysics, 754 Robinson Research Building, Vanderbilt University Medical Center, Nashville, TN 37232-0615. Email: edwin.j.weeber{at}vanderbilt.edu
The developmental lamination of the hippocampus and other cortical structures requires a signaling cascade initiated by reelin and its receptors, apoER2 (apolipoprotein E receptor 2) and VLDLR (very-low-density lipoprotein receptor). However, the functional significance of continued reelin expression in the postnatal brain remains poorly understood. Here, we show that reelin application to adult mice hippocampal slices leads to enhanced glutamatergic transmission mediated by NMDA receptors (NMDARs) and AMPA receptors (AMPARs) through distinct mechanisms. Application of recombinant reelin enhanced NMDAR-mediated currents through postsynaptic mechanisms, as revealed by the variance-mean analysis of synaptic NMDAR currents, assessment of spontaneous miniature events, and the levels of NMDAR subunits at synaptic surface. In comparison, nonstationary fluctuation analysis of miniature AMPAR currents and quantification of synaptic surface proteins revealed that reelin-induced enhancement of AMPAR responses was mediated by increased AMPAR numbers. Reelin enhancement of synaptic NMDAR currents was abolished when receptor-associated protein (RAP) or the Src inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1) was bath applied and was abrogated by including PP1 in the recording electrodes. In comparison, including RAP or an inactive PP1 analog PP3 in the recording electrode was without effect. Interestingly, the increased AMPAR response after reelin application was not blocked by PP1 but was blocked by the phosphoinositide-3' kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride]. Furthermore, reelin-induced, PI3K-dependent AMPAR surface insertion was also observed in cultured hippocampal neurons. Together, these results reveal a differential functional coupling of reelin signaling with NMDAR and AMPAR function and define a novel mechanism for controlling synaptic strength and plasticity in the adult hippocampus.
Key words: apolipoprotein receptors; long-term potentiation; Src tyrosine kinase; phosphoinositide-3 kinase; synaptic plasticity; receptor trafficking
Received June 19, 2006; revised Nov. 1, 2006; accepted Nov. 1, 2006.
Correspondence should be addressed to Dr. Edwin J. Weeber, Department of Molecular Physiology and Biophysics, 754 Robinson Research Building, Vanderbilt University Medical Center, Nashville, TN 37232-0615. Email: edwin.j.weeber{at}vanderbilt.edu
This article has been cited by other articles:
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[Abstract] [Full Text] [PDF]
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