Prefrontal cortex (PFC) is a brain region critically involved in the control of high-level """"""""executive"""""""" processes including information storage, complex reasoning, novelty seeking and emotional control. Functions of PFC neurons are strongly influenced by dopaminergic inputs. Aberrant dopaminergic actions have been implicated in PFC abnormalities associated with mental disorders such as schizophrenia. Several lines of evidence suggest that the dopamine D4 receptor, which is highly enriched in PFC neurons, plays an important and unique role in regulating PFC functions. However, little is known about the cellular mechanisms and functional consequences of D4 receptor-mediated signaling in PFC circuits. The long-term goal of this project is to understand the physiological functions of D4 receptors in PFC neurons. Particularly, we would like to elucidate how D4 signaling is involved in the regulation of synaptic transmission and plasticity in PFC, which is critical for cognitive and emotional processes. We hypothesize that D4 receptors exert an important impact on PFC functions by regulating the multifunctional Ca2+/calmodulin -dependent protein kinase II (CaMKII) and the downstream NMDA and AMPA type glutamate receptor channels. In agreement with this hypothesis, we have found that D4 receptors exert a dynamic regulation of CaMKII activity and translocation, and modulate NMDA receptor-mediated ionic and synaptic currents in a CaMKII-dependent manner. Moreover, AMPA receptor-mediated transmission and AMPA receptor internalization are also strongly regulated by D4 receptor activation. Combined electrophysiological, pharmacological, biochemical and molecular analyses will be used to extend these studies. This proposal will investigate novel mechanisms for D4 receptors to modulate PFC neuronal activity. Elucidation of these mechanisms would provide a framework for understanding how the dopaminergic and glutamatergic systems may be mechanistically linked. Such knowledge would not only offer important insights into functional roles of D4 receptors in normal PFC network, but also shed light on the development of new pharmacological agents for the treatment of many diseases associated with dopaminergic dysfunction in PFC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048911-04
Application #
7185044
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Babcock, Debra J
Project Start
2004-07-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2007
Total Cost
$309,824
Indirect Cost
Name
State University of New York at Buffalo
Department
Physiology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Yuen, Eunice Y; Wei, Jing; Liu, Wenhua et al. (2012) Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 73:962-77
Liu, Wenhua; Dou, Fei; Feng, Jian et al. (2011) RACK1 is involved in ?-amyloid impairment of muscarinic regulation of GABAergic transmission. Neurobiol Aging 32:1818-26
Hayashi-Takagi, Akiko; Takaki, Manabu; Graziane, Nick et al. (2010) Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci 13:327-32
Yuen, Eunice Y; Yan, Zhen (2009) Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex. J Neurosci 29:550-62
Yuen, Eunice Y; Ren, Yi; Yan, Zhen (2008) Postsynaptic density-95 (PSD-95) and calcineurin control the sensitivity of N-methyl-D-aspartate receptors to calpain cleavage in cortical neurons. Mol Pharmacol 74:360-70
Yuen, Eunice Y; Jiang, Qian; Chen, Paul et al. (2008) Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex. J Biol Chem 283:17194-204
Zhong, Ping; Yuen, Eunice Y; Yan, Zhen (2008) Modulation of neuronal excitability by serotonin-NMDA interactions in prefrontal cortex. Mol Cell Neurosci 38:290-9
Benavides, David R; Quinn, Jennifer J; Zhong, Ping et al. (2007) Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. J Neurosci 27:12967-76
Gu, Zhenglin; Jiang, Qian; Yan, Zhen (2007) RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. Mol Pharmacol 71:1030-9
Chen, Paul; Gu, Zhenglin; Liu, Wenhua et al. (2007) Glycogen synthase kinase 3 regulates N-methyl-D-aspartate receptor channel trafficking and function in cortical neurons. Mol Pharmacol 72:40-51

Showing the most recent 10 out of 17 publications