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

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
United States
Zip Code
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

Showing the most recent 10 out of 25 publications