Schizophrenia is a multigenic disorder where each genetic mutation contributes to subsets of the behavioral phenotypes prototypical of the disease. In order to test the hypothesis that a particular mutation contributes to schizophrenia it is essential to associate alterations in neuronal function caused by gene mutations with specific behavioral phenotypes. Here we propose to study functionally the molecular basis for olfactory dysfunction, a sensory phenotype found in a substantial fraction of schizophrenics. We hypothesize that a mutation in the promoter for the alpha7 nicotinic acetylcholine receptor contributes to diminished ability to differentiate between closely related odorants by a substantial number of schizophrenics. We show that we can study olfactory bulb neurons in humans, not only using neuroantomical techniques, but also by utilizing neuronal cultures from postmortem tissue, and we present preliminary feasibility data showing we can record nicotinic responses in these cells utilizing calcium imaging techniques. Using human olfactory bulb neurons in culture, we propose to test the hypothesis that alterations in the alpha7 nicotinic receptor promoter causes functional changes in the responses of olfactory bulb interneurons to acetylcholine that contribute to olfactory dysfunction in schizophrenics. Parallel experiments in congenic and knockout mice with altered expressionof the alpha7 acetylcholine receptor will test the link between altered responsiveness to acetylcholine and olfactory behavior. These experiments will be the first to study neuronal function in schizophrenics and controls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH068582-01A1
Application #
6969114
Study Section
Special Emphasis Panel (ZMH1-BRB-P (05))
Project Start
2004-09-27
Project End
2009-06-30
Budget Start
2004-09-27
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$273,840
Indirect Cost
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
Hutchison, Amanda K; Kelsay, Kimberly; Talmi, Ayelet et al. (2016) Thought Disorder in Preschool Children with Attention Deficit/Hyperactivity Disorder (ADHD). Child Psychiatry Hum Dev 47:618-26
Godinez, Detre A; Willcutt, Erik G; Burgess, Gregory C et al. (2015) Familial risk and ADHD-specific neural activity revealed by case-control, discordant twin pair design. Psychiatry Res 233:458-65
Sinkus, Melissa L; Graw, Sharon; Freedman, Robert et al. (2015) The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function. Neuropharmacology 96:274-88
Pellegrino, Laurel; Ross, Randal G; Hunter, Sharon K (2013) In Six-month-old Infants, Prenatal Exposure to Maternal Anxiety is Associated with Less Developed Smooth Pursuit Eye Movements: An Initial Study. Int Neuropsychiatr Dis J 1:89-103
Sparks, Tierney A; Hunter, Sharon K; Backman, Toni L et al. (2012) Maternal parenting stress and mothers' reports of their infants' mastery motivation. Infant Behav Dev 35:167-73
Stephens, Sarah H; Franks, Alexis; Berger, Ralph et al. (2012) Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia. Psychiatr Genet 22:1-14
Davalos, Deana B; Rojas, Donald C; Tregellas, Jason R (2011) Temporal processing in schizophrenia: effects of task-difficulty on behavioral discrimination and neuronal responses. Schizophr Res 127:123-30
Hunter, Sharon K; Kisley, Michael A; McCarthy, Lizbeth et al. (2011) Diminished cerebral inhibition in neonates associated with risk factors for schizophrenia: parental psychosis, maternal depression, and nicotine use. Schizophr Bull 37:1200-8
Hellier, Jennifer L; Arevalo, Nicole L; Blatner, Megan J et al. (2010) Olfactory discrimination varies in mice with different levels of ?7-nicotinic acetylcholine receptor expression. Brain Res 1358:140-50

Showing the most recent 10 out of 46 publications