The dopamine D4 receptor plays an important role in regulating functions of prefrontal cortex (PFC), a brain region critically involved in cognitive an emotional processes. A unique feature of human D4 receptor (hD4R) gene is the existence of a large number of polymorphisms in exon 3 that codes for the third intracellular loop, which consists of a variable number (2-11) of tandem repeats. Human D4R variants with long repeats have been associated with deficiencies in executive control processes in Attention Deficit and Hyperactivity Disorder (ADHD) and schizophrenia. The goal of this application is to understand the molecular and physiological basis of the polymorphism of human D4 receptors. Combined approaches will be used to test the hypothesis that hD4R variants regulate PFC glutamatergic transmission and network activity differentially by interacting with different proteins and activating distinct signaling pathways, which contributes to their different roles in mental health and disorders. Using D4R knockout mice with in vivo viral infection of hD4R variants and human D4.7R (ADHD-linked variant containing 7 repeats) knockin mice, we will reveal the impact of different human D4R variants on NMDAR trafficking and function and AMPAR-mediated synaptic transmission in PFC pyramidal neurons. Moreover, we will assess the effects of human D4R variants on synchronized network bursts, which originate from the large scale correlated activity of interconnected neurons and control selective attention. This study will significantly advance our understanding on the synaptic functions of human D4R variants and their role in mental disorders. The combined use of cutting-edge techniques enables us to effectively test the functional role of human D4R polymorphism in PFC circuits.

Public Health Relevance

Polymorphic variants of human dopamine D4 receptor have been consistently associated with ADHD; however, the molecular and physiological basis is largely unknown. Using D4R knockout mice with in vivo gene transfer, we will examine the impact of different human D4R variants on NMDAR trafficking and function, AMPAR-mediated synaptic transmission and synchronized network activity in prefrontal cortex. Results gained from study will reveal that human D4R variants regulate cortical glutamatergic transmission and circuit excitability differentially by interacting with different proteins and activating distinct signaling pathways, which may contribute to their different roles in mental health and disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1)
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Berton, Olivier Roland
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State University of New York at Buffalo
Schools of Medicine
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Seo, J-S; Zhong, P; Liu, A et al. (2018) Elevation of p11 in lateral habenula mediates depression-like behavior. Mol Psychiatry 23:1113-1119
Qin, Luye; Ma, Kaijie; Wang, Zi-Jun et al. (2018) Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci 21:564-575
Wang, Wei; Rein, Benjamin; Zhang, Freddy et al. (2018) Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome. J Neurosci 38:5939-5948
Ma, Kaijie; Qin, Luye; Matas, Emmanuel et al. (2018) Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism. Neuropsychopharmacology 43:1779-1788
Yuen, Eunice Y; Wei, Jing; Yan, Zhen (2017) Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions. Int J Neuropsychopharmacol 20:948-955
Cheng, Jia; Liu, Aiyi; Shi, Michael Y et al. (2017) Disrupted Glutamatergic Transmission in Prefrontal Cortex Contributes to Behavioral Abnormality in an Animal Model of ADHD. Neuropsychopharmacology 42:2096-2104
Zhong, Ping; Hu, Zhixing; Jiang, Houbo et al. (2017) Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations. Cell Rep 19:1033-1044
Seo, J-S; Wei, J; Qin, L et al. (2017) Cellular and molecular basis for stress-induced depression. Mol Psychiatry 22:1440-1447
Yuen, Eunice Y; Wei, Jing; Yan, Zhen (2016) Estrogen in prefrontal cortex blocks stress-induced cognitive impairments in female rats. J Steroid Biochem Mol Biol 160:221-6
Xu, Z; Jiang, H; Zhong, P et al. (2016) Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry 21:62-70

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