Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression

• Published in: Neuroscience Vol. 159; no. 1; pp. 283 - 295
• Main Authors: Lauterborn, J.C, Pineda, E, Chen, L.Y, Ramirez, E.A, Lynch, G, Gall, C.M
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 03.03.2009; Elsevier
• Subjects: AMPA receptor modulator; Analgesics, Non-Narcotic - pharmacology; Analysis of Variance; Animals; Animals, Newborn; Biological and medical sciences; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Carbachol - pharmacology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; gene expression; Hippocampus - cytology; histone deacetylase; Neurology; Neurons - cytology; neurotrophin; Oxazines - pharmacology; Protein Subunits - drug effects; Protein Subunits - genetics; Protein Subunits - metabolism; Rats; Rats, Sprague-Dawley; Receptor, trkB - genetics; Receptor, trkB - metabolism; Receptors, AMPA - drug effects; Receptors, AMPA - metabolism; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Statistics, Nonparametric; Synapses - drug effects; Synapses - metabolism; synaptic scaling; Time Factors; Tissue Culture Techniques; TrkB; Up-Regulation - drug effects; Up-Regulation - physiology; Vertebrates: nervous system and sense organs; immunoreactivity; DMSO; trichostatin A; glutamate receptor subunit; LTP; Student-Newman-Keuls; AMPA receptor modulator; SNK; dimethyl sulfoxide; analysis of variance; ANOVA; brain-derived neurotrophic factor; GluR; TSA; BDNF; ir; histone deacetylase; AMPAR; GYKI-52466; stratum; str; TrkB; AMPA receptor; 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride; synaptic scaling; neurotrophin; gene expression; long-term potentiation; Neurotrophin; Glutamate receptor; Gene expression; Subunit; Signal transduction; Synapse; trkB receptor; Brain derived neurotrophic factor; Histone
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.12.018

Abstract Recent demonstrations that positive modulators of AMPA-type glutamate receptors (ampakines) increase neuronal brain-derived neurotrophic factor (BDNF) expression have suggested a novel strategy for treating neurodegenerative diseases. However, reports that AMPA and BDNF receptors are down-regulated by prolonged activation raise concerns about the extent to which activity-induced increases in BDNF levels can be sustained without compromising glutamate receptor function. The present study constitutes an initial test of whether ampakines can cause enduring increases in BDNF content and signaling without affecting AMPA receptor (AMPAR) expression. Prolonged (12–24 h) treatment with the ampakine CX614 reduced AMPAR subunit (glutamate receptor subunit (GluR) 1-3) mRNA and protein levels in cultured rat hippocampal slices whereas treatment with AMPAR antagonists had the opposite effects. The cholinergic agonist carbachol also depressed GluR1-3 mRNA levels, suggesting that AMPAR down-regulation is a global response to extended periods of elevated neuronal activity. Analyses of time courses and thresholds indicated that BDNF expression is influenced by lower doses of, and shorter treatments with, the ampakine than is AMPAR expression. Accordingly, daily 3 h infusions of CX614 chronically elevated BDNF content with no effect on GluR1-3 concentrations. Restorative deconvolution microscopy provided the first evidence that chronic up-regulation of BDNF is accompanied by increased activation of the neurotrophin's TrkB-Fc receptor at spine synapses. These results show that changes in BDNF and AMPAR expression are dissociable and that up-regulation of the former leads to enhanced trophic signaling at excitatory synapses. These findings are encouraging with regard to the feasibility of using ampakines to tonically enhance BDNF-dependent functions in adult brain.