QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.053694v1 307/1/297    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lauterborn, J. C. Articles by Gall, C. M. Search for Related Content PubMed PubMed Citation Articles by Lauterborn, J. C. Articles by Gall, C. M.

NEUROPHARMACOLOGY

Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Departments of Anatomy and Neurobiology (J.C.L., G.S.T., C.M.G.); Neurobiology and Behavior (C.M.G.); and Psychiatry and Human Behavior, University of California, Irvine, California (M.B., X.B., G.L.); and Neuroscience Program, University of Southern California, Los Angeles, California (M.B.)

The ampakine CX614 positively modulates -amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor (BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases BDNF gene expression but with time, mRNA levels fall despite the continued presence of active drug. The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h) treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546) did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity. Finally, using a "24-h on/24-h off" CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF mRNA was induced with each ampakine application, and elevated BDNF protein levels were maintained through 5 days in vitro. These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins.

Address correspondence to: Dr. Julie C. Lauterborn, Department of Anatomy and Neurobiology, Rm. 3119, Gillespie Neuroscience Research Facility, University of California, Irvine, CA 92697-4292. E-mail: jclauter{at}uci.edu

This article has been cited by other articles:

				H. Jourdi, Y.-T. Hsu, M. Zhou, Q. Qin, X. Bi, and M. Baudry Positive AMPA Receptor Modulation Rapidly Stimulates BDNF Release and Increases Dendritic mRNA Translation J. Neurosci., July 8, 2009; 29(27): 8688 - 8697. [Abstract] [Full Text] [PDF]

				D. A. Simmons, C. S. Rex, L. Palmer, V. Pandyarajan, V. Fedulov, C. M. Gall, and G. Lynch Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice PNAS, March 24, 2009; 106(12): 4906 - 4911. [Abstract] [Full Text] [PDF]

				M. Ogier, H. Wang, E. Hong, Q. Wang, M. E. Greenberg, and D. M. Katz Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome J. Neurosci., October 3, 2007; 27(40): 10912 - 10917. [Abstract] [Full Text] [PDF]

				C. S. Rex, J. C. Lauterborn, C.-Y. Lin, E. A. Kramar, G. A. Rogers, C. M. Gall, and G. Lynch Restoration of Long-Term Potentiation in Middle-Aged Hippocampus After Induction of Brain-Derived Neurotrophic Factor J Neurophysiol, August 1, 2006; 96(2): 677 - 685. [Abstract] [Full Text] [PDF]

				H. Geerts and G. T. Grossberg Pharmacology of Acetylcholinesterase Inhibitors and N-methyl-D-aspartate Receptors for Combination Therapy in the Treatment of Alzheimer's Disease J. Clin. Pharmacol., July 1, 2006; 46(suppl_1): 8S - 16S. [Abstract] [Full Text] [PDF]

				M. M. Ramsey, M. M. Adams, O. J. Ariwodola, W. E. Sonntag, and J. L. Weiner Functional Characterization of Des-IGF-1 Action at Excitatory Synapses in the CA1 Region of Rat Hippocampus J Neurophysiol, July 1, 2005; 94(1): 247 - 254. [Abstract] [Full Text] [PDF]

				H. Jourdi, X. Lu, T. Yanagihara, J. C. Lauterborn, X. Bi, C. M. Gall, and M. Baudry Prolonged Positive Modulation of {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 16 - 26. [Abstract] [Full Text] [PDF]