Primary prevention is a goal for the investigation of any chronic illness. Project 2 focuses on translating basic neurobiological findings about the role of alpha 7 nicotinic receptors in early brain development into clinical assessments of early human developmental abnormalities that can progress to schizophrenia later in life. It is also conducting initial tests of a specific perinatal intervention to reduce this risk. We have systematically examined the development of psychophysiological and neuropsychological abnormalities associated with the genetic liability to schizophrenia in adults. These include auditory sensory gating deficits demonstrated with PSO auditory evoked potentials, abnormalities in smooth pursuit eye movements, mismatch negativity, and various measures of attention. Abnormalities in these measures appear in some children of parents with schizophrenia as soon as testing is developmentally possible. Basic science research points to the perinatal period as a critical window for the role of alpha 7 nicotinic receptors, with their maximal expression occurring then as the adult forms of GABA and glutamate synapses are expressed. We developed techniques to record PSO sensory gating within several weeks of birth and showed that this function is already normally present. In the proposed aims, we will extend our initial observation that parental history of psychosis is associated with diminished PSO auditory sensory gating. Project 3 will genotype our subjects to test whether the genetic associations of these deficits in early development are the same as the associations in adults. Similar genetic association may support the hypothesis that the deficits in children at risk for schizophrenia have the same molecular basis as deficits observed in schizophrenia itself. We will also extend a second observation that maternal nicotine use during pregnancy is associated with diminished PSO auditory sensory gating. These effects are additive with the effects of apparent genetic risk and implicate nicotinic receptors in the deficit, as is also true in adults with schizophrenia who respond to chronic nicotine exposure with loss of PSO gating. Based on Project 3's demonstration that perinatal choline, an alpha 7 nicotinic receptor agonist, improves sensory gating in the DBA/2 mouse model of genetic deficiencies in alpha 7 nicotinic receptors and sensory gating, we have obtained FDA permission to administer perinatal choline to mothers and their infants. We will continue this clinical investigation, which shows initial promise of early enhancement of sensory gating. Project 2 receives clinical research support from Project 1 and basic research support from Projects 3,4,5,6.

Public Health Relevance

New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this rprpntnr

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH086383-04S1
Application #
8515783
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
$17,115
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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