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

doi:10.1016/j.neuroscience.2008.12.018

Neuroscience

Volume 159, Issue 1, 3 March 2009, Pages 283-295

https://doi.org/10.1016/j.neuroscience.2008.12.018 Get rights and content

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.

Section snippets

Preparation of cultured hippocampal slices

Cultured hippocampal–entorhinal slices were prepared from Sprague–Dawley rat pups (9 to 11-day postnatal; Simonsen Laboratories, Gilroy, CA, USA) (n=40) as previously described (Lauterborn et al., 2000). The cultured slices included hippocampus, entorhinal cortex and portions of the adjacent neocortex. For each rat pup, slices from both hippocampi were explanted onto four Millicel-CM biomembrane inserts (Millipore, St. Louis, MO, USA) with four slices/insert and maintained with medium

Prolonged ampakine treatment decreases AMPAR subunit expression

Previous work showed that prolonged treatment with the ampakine CX614 reduces expression of the AMPAR subunits GluR1,2 (Lauterborn et al 2003, Jourdi et al 2005) but threshold conditions for eliciting changes in mRNA and protein content were not identified. To this end, the first set of experiments was designed to identify more precisely the time to decline in mRNA and protein content, to extend the analysis to GluR3 gene expression, and to identify potential differences in responses within

Discussion

The discovery that BDNF gene expression is regulated by neuronal activity raised speculation about the possibility of using drugs (Castren 2004, O'Neill et al 2004b, Lynch et al 2008) or behavioral manipulations (Cotman and Berchtold 2002, Mattson et al 2004, Gomez-Pinilla 2008) to increase brain levels of the neurotrophin with the goal of stimulating trophic signaling and enhancing plasticity. Ideas relating to this necessarily face the problem of selectivity: Is the proposed manipulation for

Acknowledgments

The authors thank Jihua Liu and Sammie Cheng for technical assistance and Cortex Pharmaceuticals Inc. (Irvine, CA, USA) for providing CX614. This research was supported in part by grants NS45260 from NINDS, CP30783 and CP40459 from Cortex Pharmaceuticals, S99-42 and bio05–10538 from the University of California Star Biotech/Discovery Programs. L.Y.C. is supported by NIMH predoctoral fellowship MH83396.

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Citation Excerpt :
In preclinical comparisons, CX614 enhanced structural plasticity and dendritic outgrowth at the same rate as ketamine,81 and also enhanced the effects of the conventional antidepressants imipramine and reboxetine.82 Other preclinical evidence demonstrated its ability to rapidly upregulate BDNF protein levels83,84 and behavioral antidepressant-like effects82,85 as well as influence the rate, frequency, and power of gamma effects in an age–drug interaction associated with spatial memory.86 In preclinical models of Huntington’s disease, CX614 prevented AMPAR desensitization, slowed deactivation, and facilitated glutamate release, significantly increasing synaptic activity by augmenting the frequency and amplitude of spontaneous and miniature excitatory postsynaptic currents (mEPSCs) in transgenic mouse models of Huntington’s chorea compared to control mice.87
Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.
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NeuropharmacologyAmpakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression

Abstract

Section snippets

Preparation of cultured hippocampal slices

Prolonged ampakine treatment decreases AMPAR subunit expression

Discussion

Acknowledgments

Exp Neurol

Curr Opin Neurobiol

Trends Neurosci

Brain Res

Neuron

J Biol Chem

Neuroscience

Ageing Res Rev

Neuroscience

Neuron

Neuron

Neuroscience

Exp Neurol

Neuroscience

Neuropharmacology

Prog Neurobiol

Curr Opin Pharmacol

Trends Neurosci

Eur J Pharmacol

Neuropharmacology

Trends Neurosci

Neuron

Eur J Pharmacol

Neuron

Neuron

Neuroscience

Mouse and rat BDNF gene structure and expression revisited

J Neurosci Res

Anterograde transport of brain-derived neurotrophic factor and its role in the brain

Nature

Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior

Curr Drug Targets

Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI-52466

Mol Pharmacol

Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ

J Neurosci

Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons

J Neurosci

Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

Proc Natl Acad Sci U S A

Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus

J Neurosci

Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons

J Neurochem

Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection

Mol Neurobiol

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