Generation of the correct numbers and types of neural cells, including neurons and astrocytes, is fundamental to normal brain development and function. Conversely, alterations in brain cell composition, especially forebrain, are considered substrate of mature mental disorders with developmental origins, such as schizophrenia, depression and autism spectrum disorder. Previously we defined positive and negative extracellular signals, including FGF, IGF1 and PACAP, and intrinsic cell cycle mechanisms that regulate neurogenesis in cerebral cortex. Using this model, we are defining mechanisms by which the neurotherapeutic valproic acid (VPA), routinely administered to women of childbearing age, affects neuro/gliogenesis, because it is a teratogen that causes malformations and contributes to neuropsychiatric disorders. We hypothesize that VPA disrupts normal brain development by differentially regulating generation of neurons and glia, altering BDNF signaling and disturbing subsequent behavioral function. We find that VPA stimulates neurogenesis in culture and in embryos via cell cycle machinery, differentially regulates gliogenesis and alters BDNF signaling.
Our Aims are: 1. Define effects of VPA on prenatal cortical neurogenesis and cell cycle machinery;2. Define VPA effects on proliferation and differentiation of astrocytes;3. Define effects of maternal VPA treatment on behavior of offspring during development and maturity. Studies will examine DNA synthesis, proliferation, differentiation, cell death, cell cycle western/RT- PCR and kinase analyses, cell composition by stereology, in culture and/or in developing pre- and postnatal animals, as well as assessments of exploratory behavior, social and anxiety measures and learning and memory processes. By defining cell type specific effects of VPA on intracellular signaling and cell cycle machinery, and characterizing consequences for brain cell composition and animal behavior during development, we may provide fundamental knowledge to effectively evaluate the benefits and risks of drug therapy, and identify pathways where intervention may counter detrimental effects of drug exposure.
Valproic acid (VPA) is routinely administered to women of childbearing age as therapy for epilepsy, mood disorders and migraine prophylaxis, raising concerns about contributions to developmental brain disorders. By defining effects on intracellular signaling, cell cycle machinery, brain cell composition and behavior, we may provide insights to evaluate VPA risks and benefits and identify pathways to prevent detrimental effects.
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