QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 18, 2005, 25(20):4974-4984; doi:10.1523/JNEUROSCI.1086-05.2005

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (51) Citing Articles via Google Scholar Google Scholar Articles by Gu, Z. Articles by Yan, Z. Search for Related Content PubMed PubMed Citation Articles by Gu, Z. Articles by Yan, Z.

 Previous Article  |  Next Article 

Cellular/Molecular
Regulation of NMDA Receptors by Neuregulin Signaling in Prefrontal Cortex

Zhenglin Gu,¹ Qian Jiang,¹ Amy K. Y. Fu,² Nancy Y. Ip,² and Zhen Yan¹

¹Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, and ²Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China

Recent linkage studies have identified a significant association of the neuregulin gene with schizophrenia, but how neuregulin is involved in schizophrenia is primarily unknown. Aberrant NMDA receptor functions have been implicated in the pathophysiology of schizophrenia. Therefore, we hypothesize that neuregulin, which is present in glutamatergic synaptic vesicles, may affect NMDA receptor functions via actions on its ErbB receptors enriched in postsynaptic densities, hence participating in emotional regulation and cognitive processes that are impaired in schizophrenia. To test this, we examined the regulation of NMDA receptor currents by neuregulin signaling pathways in prefrontal cortex (PFC), a prominent area affected in schizophrenia. We found that bath perfusion of neuregulin significantly reduced whole-cell NMDA receptor currents in acutely isolated and cultured PFC pyramidal neurons and decreased NMDA receptor-mediated EPSCs in PFC slices. The effect of neuregulin was mainly blocked by application of the ErbB receptor tyrosine kinase inhibitor, phospholipase C (PLC) inhibitor, IP₃ receptor (IP₃R) antagonist, or Ca²⁺ chelators. The neuregulin regulation of NMDA receptor currents was also markedly attenuated in cultured neurons transfected with mutant forms of Ras or a dominant-negative form of MEK1 (mitogen-activated protein kinase kinase 1). Moreover, the neuregulin effect was prevented by agents that stabilize or disrupt actin polymerization but not by agents that interfere with microtubule assembly. Furthermore, neuregulin treatment increased the abundance of internalized NMDA receptors in cultured PFC neurons, which was also sensitive to agents affecting actin cytoskeleton. Together, our study suggests that both PLC/IP₃R/Ca²⁺ and Ras/MEK/ERK (extracellular signal-regulated kinase) signaling pathways are involved in the neuregulin-induced reduction of NMDA receptor currents, which is likely through enhancing NR1 internalization via an actin-dependent mechanism.

Key words: neuregulin; ErbB receptors; NMDA receptors; schizophrenia; internalization; actin

---

Received Oct 6, 2004; revised April 13, 2005; accepted April 13, 2005.

This article has been cited by other articles:

				H. Wang, L. Song, F. Laird, P. C. Wong, and H.-K. Lee BACE1 Knock-Outs Display Deficits in Activity-Dependent Potentiation of Synaptic Transmission at Mossy Fiber to CA3 Synapses in the Hippocampus J. Neurosci., August 27, 2008; 28(35): 8677 - 8681. [Abstract] [Full Text] [PDF]

				A. Fisahn, J. Neddens, L. Yan, and A. Buonanno Neuregulin-1 Modulates Hippocampal Gamma Oscillations: Implications for Schizophrenia Cereb Cortex, July 16, 2008; (2008) bhn107v1. [Abstract] [Full Text] [PDF]

				T. Dejaegere, L. Serneels, M. K. Schafer, J. Van Biervliet, K. Horre, C. Depboylu, D. Alvarez-Fischer, A. Herreman, M. Willem, C. Haass, et al. Deficiency of Aph1B/C-{gamma}-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment PNAS, July 15, 2008; 105(28): 9775 - 9780. [Abstract] [Full Text] [PDF]

				Y.-J. J. Chen, M. A. Johnson, M. D. Lieberman, R. E. Goodchild, S. Schobel, N. Lewandowski, G. Rosoklija, R.-C. Liu, J. A. Gingrich, S. Small, et al. Type III Neuregulin-1 Is Required for Normal Sensorimotor Gating, Memory-Related Behaviors, and Corticostriatal Circuit Components J. Neurosci., July 2, 2008; 28(27): 6872 - 6883. [Abstract] [Full Text] [PDF]

				M. L. Hancock, S. E. Canetta, L. W. Role, and D. A. Talmage Presynaptic Type III Neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons J. Cell Biol., May 1, 2008; 181(3): 511 - 521. [Abstract] [Full Text] [PDF]

				H. Sheng, Y. Zhang, J. Sun, L. Gao, B. Ma, J. Lu, and X. Ni Corticotropin-Releasing Hormone (CRH) Depresses N-Methyl-D-Aspartate Receptor-Mediated Current in Cultured Rat Hippocampal Neurons via CRH Receptor Type 1 Endocrinology, March 1, 2008; 149(3): 1389 - 1398. [Abstract] [Full Text] [PDF]

				Y.-F. Wang and G. I. Hatton Interaction of Extracellular Signal-Regulated Protein Kinase 1/2 with Actin Cytoskeleton in Supraoptic Oxytocin Neurons and Astrocytes: Role in Burst Firing J. Neurosci., December 12, 2007; 27(50): 13822 - 13834. [Abstract] [Full Text] [PDF]

				P. Chen, Z. Gu, W. Liu, and Z. Yan Glycogen Synthase Kinase 3 Regulates N-Methyl-D-aspartate Receptor Channel Trafficking and Function in Cortical Neurons Mol. Pharmacol., July 1, 2007; 72(1): 40 - 51. [Abstract] [Full Text] [PDF]

				I. E. Michailidis, T. D. Helton, V. I. Petrou, T. Mirshahi, M. D. Ehlers, and D. E. Logothetis Phosphatidylinositol-4,5-Bisphosphate Regulates NMDA Receptor Activity through {alpha}-Actinin J. Neurosci., May 16, 2007; 27(20): 5523 - 5532. [Abstract] [Full Text] [PDF]

				M. Bjarnadottir, D. L. Misner, S. Haverfield-Gross, S. Bruun, V. G. Helgason, H. Stefansson, A. Sigmundsson, D. R. Firth, B. Nielsen, R. Stefansdottir, et al. Neuregulin1 (NRG1) Signaling through Fyn Modulates NMDA Receptor Phosphorylation: Differential Synaptic Function in NRG1+/- Knock-Outs Compared with Wild-Type Mice J. Neurosci., April 25, 2007; 27(17): 4519 - 4529. [Abstract] [Full Text] [PDF]

				Z. Gu, Q. Jiang, and Z. Yan RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia Mol. Pharmacol., April 1, 2007; 71(4): 1030 - 1039. [Abstract] [Full Text] [PDF]

				Q. Chang and G. D. Fischbach An Acute Effect of Neuregulin 1beta to Suppress {alpha}7-Containing Nicotinic Acetylcholine Receptors in Hippocampal Interneurons. J. Neurosci., November 1, 2006; 26(44): 11295 - 11303. [Abstract] [Full Text] [PDF]

				A. J. Law, B. K. Lipska, C. S. Weickert, T. M. Hyde, R. E. Straub, R. Hashimoto, P. J. Harrison, J. E. Kleinman, and D. R. Weinberger Neuregulin 1 Transcripts Are Differentially Expressed in Schizophrenia and Regulated by 5' SNPs Associated With the Disease Focus, August 1, 2006; 4(3): 350. [Abstract] [Full Text] [PDF]

				A. J. Law, B. K. Lipska, C. S. Weickert, T. M. Hyde, R. E. Straub, R. Hashimoto, P. J. Harrison, J. E. Kleinman, and D. R. Weinberger Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease PNAS, April 25, 2006; 103(17): 6747 - 6752. [Abstract] [Full Text] [PDF]

				O.-B. Kwon, M. Longart, D. Vullhorst, D. A. Hoffman, and A. Buonanno Neuregulin-1 Reverses Long-Term Potentiation at CA1 Hippocampal Synapses J. Neurosci., October 12, 2005; 25(41): 9378 - 9383. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help