Schizophrenia is a disease of unknown etiology which does not occur in animals. However, some aspects of the disorder are amenable to study in both animals and schizophrenia patients. An example is abnormal processing of sensory information; a hallmark of schizophrenia. Schizophrenics concentrate poorly and are often overloaded by incoming sensory information. The resultant flood of input may lead to personality decompensation. Deficient sensory processing can be assessed in both humans and animals using a conditioning-test paradigm and comparing the electrophysiological responses to paired auditory stimuli. Normal humans and most mouse strains show a reduced response to the second stimulus, thus, they are filtering or """"""""gating"""""""" their response to this stimulus. Schizophrenia patients, some of their first degree relatives, and certain inbred mouse strains show responses to both stimuli which are of the same magnitude; thus, they do not gate. Traditional neuroleptic treatment does not normalize the gating deficit in schizophrenics, however, recent studies in both humans and animals have demonstrated involvement of the nicotinic receptor, specifically the alpha7 subtype, in the modulation of sensory gating. In a recent study of human pedigrees, the gating deficit was shown to be linked to chromosomal position 15q13-14, the site to which the human alpha7 receptor maps. Thus, data suggest that the alpha7 nicotinic receptor may be modulating auditory gating in both humans and rodents, however, other systems cannot be ruled out. In a classical breeding study using 2 strains of inbred mice, gating capacity was shown to be a heritable trait with a single gene, autosomal dominant pattern. This proposal will seek to identify chromosomal loci in the mouse genome which are linked to the auditory gating deficit. The segregation data suggesting the single gene model used a cross between the C3H mouse (a gating strain) and the DBA/2 mouse (a non-gating strain). I have a significant volume of data on auditory gating with the parental strains, F1, F2 and backcross generations, and the current proposal would extent these studies as well as assess the relationship between an identified restriction fragment length polymorphism (RFLP), near the alpha7 nicotinic receptor gene in the mouse, and auditory gating (Expt. 1). Also, a full genome scan will attempt to link auditory gating with any other chromosomal loci (Expt. 2). Another study will assess auditory gating and linkage to any loci in a second genetic cross between C57BL/6 mice (a gating strain) and DBA/2 mice, allowing assessment of the DBA/2 gating pattern on another genetic background with the same RFLP as C3H mice. This cross also has recombinant inbred (RI) strains which allows precise determination of gating for each RI strain. Part of the variance in auditory gating is non-genetic, and assessment of RI strains will reduce this component. In addition, assessment of true F2 generation mice will confirm sites identified in the RI strain study (Expt. 3). Identified loci in mice may lead to isolation of the gene(s) controlling schizophrenia in humans. Such information could be important in understanding of the etiology of the disorder and in determining future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH058680-03
Application #
6392375
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Farmer, Mary E
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$191,504
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Simosky, Johanna K; Freedman, Robert; Stevens, Karen E (2008) Olanzapine improves deficient sensory inhibition in DBA/2 mice. Brain Res 1233:129-36