Dysfunction of the mesocortical neurotransmitter systems has been implicated in many neurological and mental disorders, including schizophrenia, depression and anxiety. Increasing evidence has suggested that many of these diseases result from altered serotonergic pathways and their dysregulation of neuronal activity in prefrontal cortex (PFC), a critical brain region controlling cognition and emotion. Many novel antipsychotic agents, antidepressants and anxiolytics act on serotonin receptors in PFC neurons. Understanding molecular and cellular mechanisms underlying the actions of serotonin in PFC is crucial for designing more effective therapeutic strategies in the treatment of brain disorders. Despite considerable progress on understanding the significance of serotonin at the system level, how serotonin regulates cellular excitability and synaptic function of PFC neurons remains unclear. It is our long-term goal to understand the molecular and cellular mechanisms of serotonin signaling in prefrontal cortex. Serotonin exerts its actions mainly through a complex set of G protein-coupled receptors. PFC is composed of glutamatergic pyramidal neurons and GABAergic interneurons. AMPA-type glutamate receptors and GABAA receptors, both of which contain intrinsic ion channels, are major players mediating excitatory and inhibitory synaptic transmission respectively in PFC. It is my working hypothesis that GABAA receptor channels and AMPA receptor channels are two major targets of the serotonin system. Serotonin plays a pivotal role in the regulation of PFC functions by suppressing GABAergic inhibitory activity and potentiating counterbalancing glutamatergic neurotransmission in PFC neurons through different 5-HT receptor-mediated signaling cascades. To characterize the signal transduction mechanisms underlying the serotonergic modulation of these channels in PFC neurons, a combination of electrophysiological, pharmacological and molecular approaches will be used. The coordinated expression and subcellular localization of serotonin receptors in PFC neurons will be determined using single-cell mRNA profiling and immunocytochemistry methods. The effect of serotonin on the biophysical properties of GABAA and AMPA receptor channels will be studied using patch-clamp analyses of PFC neurons. The intracellular signaling pathways utilized by serotonin to modulate these channels will be revealed using pharmacological tools, molecular and biochemical assays. This study will provide important insights into the molecular and cellular mechanisms underlying serotonergic regulation of cellular activity and synaptic transmission in PFC neurons. Knowledge gained from this work would contribute to the development of novel therapeutic strategies for many neurological and mental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063128-04
Application #
6824877
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Winsky, Lois M
Project Start
2001-12-07
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2005
Total Cost
$274,750
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
Chen, Guojun; Chen, Paul; Tan, Huibing et al. (2008) Regulation of the NMDA receptor-mediated synaptic response by acetylcholinesterase inhibitors and its impairment in an animal model of Alzheimer's disease. Neurobiol Aging 29:1795-804
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
Liu, Wenhua; Yuen, Eunice Y; Allen, Patrick B et al. (2006) Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Proc Natl Acad Sci U S A 103:18338-43
Wang, Xun; Gu, Zhenglin; Zhong, Ping et al. (2006) Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure. Mol Cell Neurosci 31:15-25
Chen, Guojun; Kittler, Josef T; Moss, Stephen J et al. (2006) Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens. J Neurosci 26:2513-21
Gu, Zhenglin; Jiang, Qian; Yuen, Eunice Y et al. (2006) Activation of dopamine D4 receptors induces synaptic translocation of Ca2+/calmodulin-dependent protein kinase II in cultured prefrontal cortical neurons. Mol Pharmacol 69:813-22

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