PMID- 19141314
OWN - NLM
STAT- MEDLINE
DCOM- 20090625
LR  - 20211020
IS  - 0306-4522 (Print)
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 159
IP  - 1
DP  - 2009 Mar 3
TI  - Ampakines cause sustained increases in brain-derived neurotrophic factor 
      signaling at excitatory synapses without changes in AMPA receptor subunit 
      expression.
PG  - 283-95
LID - 10.1016/j.neuroscience.2008.12.018 [doi]
AB  - 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.
FAU - Lauterborn, J C
AU  - Lauterborn JC
AD  - Department of Anatomy and Neurobiology, Gillespie Neuroscience Research Facility 
      (Room 3119), 837 Health Science Drive, University of California at Irvine, 
      Irvine, CA 92697-4291, USA.
FAU - Pineda, E
AU  - Pineda E
FAU - Chen, L Y
AU  - Chen LY
FAU - Ramirez, E A
AU  - Ramirez EA
FAU - Lynch, G
AU  - Lynch G
FAU - Gall, C M
AU  - Gall CM
LA  - eng
GR  - P01 NS045260-01A10001/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-01A19001/NS/NINDS NIH HHS/United States
GR  - F31 MH083396/MH/NIMH NIH HHS/United States
GR  - P01 NS045260-029001/NS/NINDS NIH HHS/United States
GR  - P01 NS045260/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-02/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-03/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-049001/NS/NINDS NIH HHS/United States
GR  - MH83396/MH/NIMH NIH HHS/United States
GR  - P01 NS045260-01A1/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-059001/NS/NINDS NIH HHS/United States
GR  - NS45260/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-04/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-039001/NS/NINDS NIH HHS/United States
GR  - P01 NS045260-05/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20081224
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Analgesics, Non-Narcotic)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Oxazines)
RN  - 0 (Protein Subunits)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, AMPA)
RN  - 87V631480W (2H,3H,6aH-pyrrolidino(2'',1''-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1, 
      4-dioxan-10-one)
RN  - 8Y164V895Y (Carbachol)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Analgesics, Non-Narcotic/pharmacology
MH  - Analysis of Variance
MH  - Animals
MH  - Animals, Newborn
MH  - Brain-Derived Neurotrophic Factor/*genetics/metabolism
MH  - Carbachol/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Hippocampus/cytology
MH  - Neurons/cytology
MH  - Oxazines/*pharmacology
MH  - Protein Subunits/drug effects/genetics/metabolism
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/genetics/metabolism
MH  - Receptors, AMPA/*drug effects/metabolism
MH  - Signal Transduction/*drug effects/physiology
MH  - Statistics, Nonparametric
MH  - Synapses/*drug effects/metabolism
MH  - Time Factors
MH  - Tissue Culture Techniques
MH  - Up-Regulation/*drug effects/physiology
PMC - PMC2746455
MID - NIHMS84788
EDAT- 2009/01/15 09:00
MHDA- 2009/06/26 09:00
PMCR- 2010/03/03
CRDT- 2009/01/15 09:00
PHST- 2008/07/19 00:00 [received]
PHST- 2008/11/27 00:00 [revised]
PHST- 2008/11/06 00:00 [accepted]
PHST- 2009/01/15 09:00 [entrez]
PHST- 2009/01/15 09:00 [pubmed]
PHST- 2009/06/26 09:00 [medline]
PHST- 2010/03/03 00:00 [pmc-release]
AID - S0306-4522(08)01765-X [pii]
AID - 10.1016/j.neuroscience.2008.12.018 [doi]
PST - ppublish
SO  - Neuroscience. 2009 Mar 3;159(1):283-95. doi: 10.1016/j.neuroscience.2008.12.018. 
      Epub 2008 Dec 24.