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The Journal of Neuroscience, October 7, 2009, 29(40):12702-12710; doi:10.1523/JNEUROSCI.1166-09.2009

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Cellular/Molecular
Autocrine Activation of Neuronal NMDA Receptors by Aspartate Mediates Dopamine- and cAMP-Induced CREB-Dependent Gene Transcription

Luis E. F. Almeida,¹ Peter D. Murray,^1,5 H. Ronald Zielke,² Clinton D. Roby,¹ Tami J. Kingsbury,^1,4,5 and Bruce K. Krueger^1,3,5

Departments of ¹Physiology, ²Pediatrics, and ³Psychiatry, ⁴Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, and ⁵Program in Neuroscience, University of Maryland Baltimore, Baltimore, Maryland 21201

Correspondence should be addressed to Bruce K. Krueger, Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201. Email: bkrueger{at}umaryland.edu

cAMP can stimulate the transcription of many activity-dependent genes via activation of the transcription factor, cAMP response element-binding protein (CREB). However, in mouse cortical neuron cultures, prior to synaptogenesis, neither cAMP nor dopamine, which acts via cAMP, stimulated CREB-dependent gene transcription when NR2B-containing NMDA receptors (NMDARs) were blocked. Stimulation of transcription by cAMP was potentiated by inhibitors of excitatory amino acid uptake, suggesting a role for extracellular glutamate or aspartate in cAMP-induced transcription. Aspartate was identified as the extracellular messenger: enzymatic scavenging of L-aspartate, but not glutamate, blocked stimulation of CREB-dependent gene transcription by cAMP; moreover, cAMP induced aspartate but not glutamate release. Together, these results suggest that cAMP acts via an autocrine or paracrine pathway to release aspartate, which activates NR2B-containing NMDARs, leading to Ca²⁺ entry and activation of transcription. This cAMP/aspartate/NMDAR signaling pathway may mediate the effects of transmitters such as dopamine on axon growth and synaptogenesis in developing neurons or on synaptic plasticity in mature neural networks.

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Received March 10, 2009; revised Aug. 6, 2009; accepted Sept. 2, 2009.

Correspondence should be addressed to Bruce K. Krueger, Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201. Email: bkrueger{at}umaryland.edu

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