Deficits in sensory inhibition are a common symptom of schizophrenia and are correlated with certain positive symptoms. Improvement in symptomology is seen concurrent with improvement in sensory nhibition. The sensory inhibition deficit has been modeled in DBA/2 mice which not only show the deficient sensory inhibition, but are also genotypically similar to schizophrenics in having reduced numbers of alpha7 nicotinic receptors in the hippocampus and polymorphisms in the gene coding. We have recently shown that perinatal choline supplementation in the diet of the dam, produces DBA/2 offpspring with normal sensory nhibition. Perinatal choline supplementation in rats and one mouse strain (C57/BL6) has previously been shown to improve learning and memory in offspring thoughout their lifetimes. Our preliminary data show that sensory inhibition circuitry is also permanently altered in that there is a significant increase in apha7 nicotinic receptors in the dentate gyrus and CA1 regions of the hippocampus with peri-natal choline supplementation. The underlying mechanism of the improved sensory inhibition is not known. The present application will seek to elucidate the mechanism(s) by assessing role of alpha/ receptors (using alpha7 null mutant mice), the role of non-alpha7 receptors (using an agonist at both alpha7 and non-alpha7 receptors compared to an agonist at alpha7 receptors which is also an antagonist at alpha4beta2 receptors), and the role of DNA methylation (using an alternate methyl donor, and additionally, a genetically altered mouse strain with hypermethylation). Since learning and memory effects have been observed with peri-natal choline administration, all groups will be tested for learning and memory alterations. Finally, any changes in hippocampal alpha7 receptor levels induced by any of the perinatal interventions as well as the hypermethylation mice mice will be assessed using quantitative autoradiography. The data from these studies may potentially impact guide lines for human prenatal nutrition in at-risk pregnancies for schizophrenia. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH073725-01A2
Application #
7147798
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Winsky, Lois M
Project Start
2006-08-15
Project End
2009-07-31
Budget Start
2006-08-15
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$241,472
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Schulz, Kalynn M; Pearson, Jennifer N; Gasparrini, Mary E et al. (2014) Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors. Behav Brain Res 268:104-10
Wildeboer-Andrud, Kristin M; Stevens, Karen E (2011) The smoking cessation drug varenicline improves deficient P20-N40 inhibition in DBA/2 mice. Pharmacol Biochem Behav 100:17-24
Schulz, Kalynn M; Pearson, Jennifer N; Neeley, Eric W et al. (2011) Maternal stress during pregnancy causes sex-specific alterations in offspring memory performance, social interactions, indices of anxiety, and body mass. Physiol Behav 104:340-7
Stevens, Karen E; Cornejo, Brandon; Adams, Catherine E et al. (2010) Continuous administration of a selective alpha7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice. Brain Res 1352:140-6
Ross, Randal G; Stevens, Karen E; Proctor, William R et al. (2010) Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia. J Child Psychol Psychiatry 51:535-49
Wildeboer, Kristin M; Zheng, Lijun; Choo, Kevin S et al. (2009) Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism. Brain Res 1300:41-50
Abrams, Daniel J; Zheng, Lijun; Choo, Kevin S et al. (2008) An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients. Schizophr Res 100:86-96
Wildeboer, Kristin M; Stevens, Karen E (2008) Stimulation of the alpha4beta2 nicotinic receptor by 5-I A-85380 improves auditory gating in DBA/2 mice. Brain Res 1224:29-36
Stevens, Karen E; Adams, Catherine E; Yonchek, Joan et al. (2008) Permanent improvement in deficient sensory inhibition in DBA/2 mice with increased perinatal choline. Psychopharmacology (Berl) 198:413-20
Stevens, Karen E; Adams, Catherine E; Mellott, Tiffany J et al. (2008) Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats. Brain Res 1237:84-90

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