Neuropsychiatric disorders affect 25% of the population sometime during their life. Aberrant dendritic arbors appear in mental disorders. Although the psychopathological mechanisms are not completely understood, it has been suggested that changes in gene expression contribute to the development and therapy. Several evidences, including the applicant own studies, suggest that misregulation of Sp4 transcription factor could be involved in the pathogenesis and therapy of affective disorders by controlling dendritic patterning. The applicant will explore the possibility that Sp4 and other transcriptional regulators might be altered in postmortem human brains of patients with mental disorders. This research pretends also to investigate the capability to regulate dendritic development by altered novel factors and psychotropic treatment. This project we will test the hypothesis that mood stabilizer and antipsychotic drug leads to a physiological dendritic patterning, in part, through the stabilization/activation of Sp4 transcription factor which leads to changes in expression of genes important for the pathogenesis and therapy of neuropsichiatric disorders. To address that hypothesis (a) we will study whether the levels of Sp4 transcription factor protein or other factors are altered in postmortem brain tissue from patients with schizophrenia or affective disorders. (b) We will perform a novel quantitative proteomic approach (SILAC) and gene expression arrays in postmortem brain of neuropsychiatric patients and whether the new hits module dendritic patterning. (c) And also, we will study the effect of mood stabilizers and antipsychotics on dendritic morphology by Sp4-dependent mechanism. These studies will give a new insight in the transcriptional programs controlled by lithium which may regulate dendritic morphology and, will provide the regulation of Sp4 u others factors as a possible mechanism involved in the pathogenesis and therapy of neuropsychiatric disorders.
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