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The Journal of Neuroscience, January 1, 2000, 20(1):8-21
Positive Modulation of AMPA Receptors Increases Neurotrophin
Expression by Hippocampal and Cortical Neurons
Julie C.
Lauterborn1,
Gary
Lynch2,
Peter
Vanderklish3,
Amy
Arai2, and
Christine M.
Gall1, 3
Departments of 1 Anatomy and Neurobiology,
2 Psychiatry and Human Behavior, and
3 Psychobiology, University of California, Irvine,
California 92697-4292
This study investigated whether positive modulators of AMPA-type
glutamate receptors influence neurotrophin expression by forebrain
neurons. Treatments with the ampakine CX614 markedly and reversibly
increased brain-derived neurotrophic factor (BDNF) mRNA and protein
levels in cultured rat entorhinal/hippocampal slices. Acute effects of
CX614 were dose dependent over the range in which the drug increased
synchronous neuronal discharges; threshold concentrations for acute
responses had large effects on mRNA content when applied for 3 d.
Comparable results were obtained with a second, structurally distinct
ampakine CX546. Ampakine-induced upregulation was broadly suppressed by
AMPA, but not NMDA, receptor antagonists and by reducing transmitter
release. Antagonism of L-type voltage-sensitive calcium channels
blocked induction in entorhinal cortex but not hippocampus. Prolonged
infusions of suprathreshold ampakine concentrations produced peak BDNF
mRNA levels at 12 hr and a return to baseline levels by 48 hr. In
contrast, BDNF protein remained elevated throughout a 48 hr incubation
with the drug. Nerve growth factor mRNA levels also were increased by
ampakines but with a much more rapid return to control levels during
chronic administration. Finally, intraperitoneal injections of CX546
increased hippocampal BDNF mRNA levels in aged rats and middle-aged
mice. The present results provide evidence of regional differences in
mechanisms via which activity regulates neurotrophin expression.
Moreover, these data establish that changes in synaptic potency produce
sufficient network level physiological effects for inducing
neurotrophin genes, indicate that the response becomes refractory
during prolonged ampakine exposure, and raise the possibility of using
positive AMPA modulators to regulate neurotrophin levels in aged brain.
Key words:
brain-derived neurotrophic factor; nerve growth factor; ampakine; hippocampus; gene regulation; trkB; aging
Copyright © 2000 Society for Neuroscience 0270-6474/0/2018-14$05.00/0
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