REELIN DEFICIENCY--MODEL FOR SCHIZOPHRENIA VULNERABILITY

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DESCRIPTION: (Adapted from the Investigator's Abstract) 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.