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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-F)
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University of Colorado Denver
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Wilking, Jennifer A; Stitzel, Jerry A (2015) Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds. Neuropharmacology 96:205-12
Bates, R C; Stith, B J; Stevens, K E et al. (2014) Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. Neuroscience 273:52-64
Stevens, Karen E; Choo, Kevin S; Stitzel, Jerry A et al. (2014) Long-term improvements in sensory inhibition with gestational choline supplementation linked to ?7 nicotinic receptors through studies in Chrna7 null mutation mice. Brain Res 1552:26-33
McClure-Begley, Tristan D; Grady, Sharon R; Marks, Michael J et al. (2014) Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes. Biochem Pharmacol 91:87-96
Wildeboer-Andrud, Kristin M; Zheng, Lijun; Choo, Kevin S et al. (2014) Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude. Pharmacol Biochem Behav 117:144-50
Law, Amanda J (2014) Genetic mouse models of neuregulin 1: gene dosage effects, isoform-specific functions, and relevance to schizophrenia. Biol Psychiatry 76:89-90
Tregellas, Jason R (2014) Neuroimaging biomarkers for early drug development in schizophrenia. Biol Psychiatry 76:111-9
Tregellas, Jason R; Smucny, Jason; Harris, Josette G et al. (2014) Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia. Am J Psychiatry 171:549-56
Paterson, Clare; Wang, Yanhong; Kleinman, Joel E et al. (2014) Effects of schizophrenia risk variation in the NRG1 gene on NRG1-IV splicing during fetal and early postnatal human neocortical development. Am J Psychiatry 171:979-89
Smucny, Jason; Stevens, Karen E; Tregellas, Jason R (2014) Acute administration of ?? tetrahydrocannabinol does not prevent enhancement of sensory gating by clozapine in DBA/2 mice. Pharmacol Biochem Behav 118:22-9

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