Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia- 1

Zhen Yan, Jing Wei, Nicholas M. Graziane, Haitao Wang, Ping Zhong, Qi Wang, Wenhua Liu, Akiko Hayashi-Takagi, Carsten Korth, Akira Sawa, Nicholas J. Brandon

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Abstract

Background Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1. Methods DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured. Results We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters. Conclusions Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

Original languageEnglish (US)
Pages (from-to)414-424
Number of pages11
JournalBiological Psychiatry
Volume75
Issue number5
DOIs
StatePublished - Mar 1 2014

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N-Methyl-D-Aspartate Receptors
Schizophrenia
Cyclic AMP-Dependent Protein Kinases
CREB-Binding Protein
Type 4 Cyclic Nucleotide Phosphodiesterase
Phosphodiesterase 4 Inhibitors
Pyramidal Cells
Response Elements
Protein Kinase Inhibitors
Cyclic AMP
RNA

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Yan, Zhen ; Wei, Jing ; Graziane, Nicholas M. ; Wang, Haitao ; Zhong, Ping ; Wang, Qi ; Liu, Wenhua ; Hayashi-Takagi, Akiko ; Korth, Carsten ; Sawa, Akira ; Brandon, Nicholas J. / Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia- 1. In: Biological Psychiatry. 2014 ; Vol. 75, No. 5. pp. 414-424.
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abstract = "Background Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1. Methods DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured. Results We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters. Conclusions Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.",
author = "Zhen Yan and Jing Wei and Graziane, {Nicholas M.} and Haitao Wang and Ping Zhong and Qi Wang and Wenhua Liu and Akiko Hayashi-Takagi and Carsten Korth and Akira Sawa and Brandon, {Nicholas J.}",
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Yan, Z, Wei, J, Graziane, NM, Wang, H, Zhong, P, Wang, Q, Liu, W, Hayashi-Takagi, A, Korth, C, Sawa, A & Brandon, NJ 2014, 'Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia- 1', Biological Psychiatry, vol. 75, no. 5, pp. 414-424. https://doi.org/10.1016/j.biopsych.2013.06.009

Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia- 1. / Yan, Zhen; Wei, Jing; Graziane, Nicholas M.; Wang, Haitao; Zhong, Ping; Wang, Qi; Liu, Wenhua; Hayashi-Takagi, Akiko; Korth, Carsten; Sawa, Akira; Brandon, Nicholas J.

In: Biological Psychiatry, Vol. 75, No. 5, 01.03.2014, p. 414-424.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia- 1

AU - Yan, Zhen

AU - Wei, Jing

AU - Graziane, Nicholas M.

AU - Wang, Haitao

AU - Zhong, Ping

AU - Wang, Qi

AU - Liu, Wenhua

AU - Hayashi-Takagi, Akiko

AU - Korth, Carsten

AU - Sawa, Akira

AU - Brandon, Nicholas J.

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Y1 - 2014/3/1

N2 - Background Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1. Methods DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured. Results We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters. Conclusions Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

AB - Background Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1. Methods DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured. Results We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters. Conclusions Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

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