Telencephalic brain structures are known to follow an unusually complex course of embryological developmental in which RELN plays a pivotal signaling role. In this project, we want to establish whether in postnatal and adult mice genetic RELN deficiency (RELN haploinsufficiency) leads to the expression of progressive and region-specific brain abnormalities and whether some of the abnormalities resemble caricatures of the alterations observed in the brain of schizophrenic patients. We have selected the heterozygous reeler mutant (rl +/-) mouse as a model of RELN haploinsufficiency. In preliminary experiments we have shown that in adult rl +/- mice, in addition to a lower than normal RELN expression there are a number of microanatomical and neurophysiological abnormalities reminiscent of schizophrenia. Thus, we propose to 1) compare whether RELN expression and neuronal location are similar in rl +/- and wild-type (wt) mice; 2) determine whether RELN haploinsufficiency elicits changes in the relationship existing between RELN haploinsufficiency and altered cortical distribution of GABAergic interneurons, decrease of GAD67 expression and decrease in neuropil density; 3) study if there is a progression of these changes with age, or if these changes are restricted to cortex or are present in other brain areas that are also affected in schizophrenia; and 4) examine if RELN haploinsufficiency is a vulnerability factor that predisposes peripubertal mice to an incidence of behavioral and microanatomical abnormalities when exposed to noxious insults such as social isolation stress. Although the putative interaction of RELN haploinsufficiency with epigenetic factors occurring in schizophrenic patients probably differs from the factors operative in socially isolated mice, study of the murine model may reveal those mechanisms of neurodevelopment that are likely to be disrupted by RELN deficiency in the brain of schizophrenic patients. The understanding of RELN expression regulation in adult brain may be of great importance in the design of pharmacological tools to correct RELN brain insufficiency and to reduce the behavioral and microanatomical abnormalities associated to this deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062188-03
Application #
6528828
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Winsky, Lois M
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$271,775
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Auta, James; Impagnatiello, Francesco; Kadriu, Bashkim et al. (2008) Imidazenil: a low efficacy agonist at alpha1- but high efficacy at alpha5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem. Neuropharmacology 55:148-53
Sharma, Rajiv P; Rosen, Cherise; Kartan, Saritha et al. (2006) Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: preliminary results from a clinical population. Schizophr Res 88:227-31
Veldic, Marin; Guidotti, Alessandro; Maloku, Ekrem et al. (2005) In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc Natl Acad Sci U S A 102:2152-7
Dong, E; Agis-Balboa, R C; Simonini, M V et al. (2005) Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc Natl Acad Sci U S A 102:12578-83
Tremolizzo, Lucio; Doueiri, Mohemed-Salim; Dong, Erbo et al. (2005) Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biol Psychiatry 57:500-9
Ilijic, E; Guidotti, A; Mugnaini, E (2005) Moving up or moving down? Malpositioned cerebellar unipolar brush cells in reeler mouse. Neuroscience 136:633-47
Noh, Jai Sung; Sharma, Rajiv P; Veldic, Marin et al. (2005) DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci U S A 102:1749-54
Guidotti, Alessandro; Auta, James; Davis, John M et al. (2005) GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology (Berl) 180:191-205
Grayson, Dennis R; Jia, Xiaomei; Chen, Ying et al. (2005) Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A 102:9341-6
Sharma, Rajiv P; Grayson, Dennis R; Guidotti, Alessandro et al. (2005) Chromatin, DNA methylation and neuron gene regulation--the purpose of the package. J Psychiatry Neurosci 30:257-63

Showing the most recent 10 out of 23 publications