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The Journal of Neuroscience, June 24, 2009, 29(25):8215-8224; doi:10.1523/JNEUROSCI.1773-09.2009

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Behavioral/Systems/Cognitive
Hyperdopaminergia and NMDA Receptor Hypofunction Disrupt Neural Phase Signaling

Kafui Dzirasa,¹ Amy J. Ramsey,² Daniel Yasumasa Takahashi,^6,7 Jennifer Stapleton,¹ Juan M. Potes,¹ Jamila K. Williams,¹ Raul R. Gainetdinov,² Koichi Sameshima,^6,7 Marc G. Caron,² and Miguel A. L. Nicolelis^1,3,4,5,6

¹Departments of Neurobiology, ²Cell Biology, ³Psychology and Neuroscience, and ⁴Biomedical Engineering and ⁵Center for Neuroengineering, Duke University Medical Center, Durham, North Carolina 27710, ⁶Edmond and Lily Safra International Institute of Neuroscience of Natal, 59066-060 Natal, Brazil, and ⁷Bioinformatics Graduate Program and Department of Radiology, School of Medicine, University of São Paulo, 01246-903 São Paulo SP, Brazil

Correspondence should be addressed to Kafui Dzirasa, Department of Neurobiology, Duke University Medical Center, Bryan Research Building, Durham, NC 27710. Email: dzirasa{at}neuro.duke.edu

Neural phase signaling has gained attention as a putative coding mechanism through which the brain binds the activity of neurons across distributed brain areas to generate thoughts, percepts, and behaviors. Neural phase signaling has been shown to play a role in various cognitive processes, and it has been suggested that altered phase signaling may play a role in mediating the cognitive deficits observed across neuropsychiatric illness. Here, we investigated neural phase signaling in two mouse models of cognitive dysfunction: mice with genetically induced hyperdopaminergia [dopamine transporter knock-out (DAT-KO) mice] and mice with genetically induced NMDA receptor hypofunction [NMDA receptor subunit-1 knockdown (NR1-KD) mice]. Cognitive function in these mice was assessed using a radial-arm maze task, and local field potentials were recorded from dorsal hippocampus and prefrontal cortex as DAT-KO mice, NR1-KD mice, and their littermate controls engaged in behavioral exploration. Our results demonstrate that both DAT-KO and NR1-KD mice display deficits in spatial cognitive performance. Moreover, we show that persistent hyperdopaminergia alters interstructural phase signaling, whereas NMDA receptor hypofunction alters interstructural and intrastructural phase signaling. These results demonstrate that dopamine and NMDA receptor dependent glutamate signaling play a critical role in coordinating neural phase signaling, and encourage further studies to investigate the role that deficits in phase signaling play in mediating cognitive dysfunction.

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Received April 13, 2009; revised May 18, 2009; accepted May 20, 2009.

Correspondence should be addressed to Kafui Dzirasa, Department of Neurobiology, Duke University Medical Center, Bryan Research Building, Durham, NC 27710. Email: dzirasa{at}neuro.duke.edu

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