The mouse models of alpha? nicotinic receptor dysfunction of Project 4 have led to significant understanding of the role of allelic variants in the gene for this receptor in development and function of the hippocampus, particulary in regard to its role in auditory sensory gating;the possible therapeutiuc effects of nicotinic agonists on sensory gating dysfunction in schizophrenia;and the possible preventive effect of perinatal intervention with choline supplementation. As the discoveries of Project 4 are translated into clinical studies by Projects 1 and 2, possible limitations reflecting the differences between human CHRNA? and mouse Chrna? must be considered. Therfore Project 5 will attempt to produce a mouse that has the human CHRNA? in place of the mouse gene, using homologous recombination in mouse embyonic stem cells. This technique will allow us to study differences between the mouse and human gene in Experiment 1, to assess the effects of variants in the gene found in schizophrenia by Project 3 in Experiment 2, and to determine the effect of choline on the development of neurons that have human versions of CHRNA? and the alpha 7 nicotinic receptor in Experiment 3 to help Project 2 design the safest and most effective human treatment. Although production of a transgenic mouse is always a high risk project, the Center's history of successful translational use of research findings in animal models to shape clinical trials now supports this enhancement of its animal model of the genetic basis of a? nicotinic receptor dysfunction. Project 5 supports clinical research in Projects 1 and 2 and receives genetic resources frim Project 3, phenotyping support from Project 4, and will interact with Project 6 to examine effects of maternal immune activation.

Public Health Relevance

New therapeutic strageties for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center examines a dysfunctioning nicotinic acetylcholine receptor as a new therapeutic target. It investigates a new drug treatment for schizophrenia and a preventative nutrient intervention during early infant development, both of which activate this receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH086383-04S1
Application #
8515797
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$17,114
Indirect Cost
$6,004
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Hutchison, Amanda K; Hunter, Sharon K; Wagner, Brandie D et al. (2017) Diminished Infant P50 Sensory Gating Predicts Increased 40-Month-Old Attention, Anxiety/Depression, and Externalizing Symptoms. J Atten Disord 21:209-218
Wu, Wei-Li; Hsiao, Elaine Y; Yan, Zihao et al. (2017) The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun 62:11-23
Paterson, Clare; Wang, Yanhong; Hyde, Thomas M et al. (2017) Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders. Am J Psychiatry 174:256-265
Papaleo, Francesco; Yang, Feng; Paterson, Clare et al. (2016) Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. J Neurosci 36:4859-75
Ross, Randal G; Hunter, Sharon K; Hoffman, M Camille et al. (2016) Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. Am J Psychiatry 173:509-16
Chow, Ke-Huan; Yan, Zihao; Wu, Wei-Li (2016) Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic Poly(I:C). J Vis Exp :e53643
D'Anna-Hernandez, Kimberly L; Garcia, Esmeralda; Coussons-Read, Mary et al. (2016) Sleep Moderates and Mediates the Relationship Between Acculturation and Depressive Symptoms in Pregnant Mexican-American Women. Matern Child Health J 20:422-33
Stevens, Karen E; Zheng, Lijun; Floyd, Kirsten L et al. (2015) Maximizing the effect of an ?7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits. Brain Res 1611:8-17
Lester, Henry A; Lavis, Luke D; Dougherty, Dennis A (2015) Ketamine inside neurons? Am J Psychiatry 172:1064-6
Horton, William J; Gissel, Hannah J; Saboy, Jennifer E et al. (2015) Melatonin administration alters nicotine preference consumption via signaling through high-affinity melatonin receptors. Psychopharmacology (Berl) 232:2519-30

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