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VPA is a well\u2010known teratogen that produces congenital malformations in many organs including the nervous system, as well as later neurodevelopmental disorders, including mental retardation and autism. In developing brain, few studies have examined VPA effects on glial cells, particularly astrocytes. To investigate effects on primary glial precursors, we developed new cell culture and <jats:italic>in vivo<\/jats:italic> models using frontal cerebral cortex of postnatal day (P2) rat. <jats:italic>In vitro<\/jats:italic>, VPA exposure elicited dose\u2010dependent, biphasic effects on DNA synthesis and proliferation. <jats:italic>In vivo<\/jats:italic> VPA (300\u00a0mg\/kg) exposure from P2 to P4 increased both DNA synthesis and cell proliferation, affecting primarily astrocyte precursors, as &gt;75% of mitotic cells expressed brain lipid\u2010binding protein. Significantly, the consequence of early VPA exposure was increased astrocytes, as both S100\u2010\u03b2+ cells and glial fibrillary acidic protein were increased in adolescent brain. Molecularly, VPA served as an HDAC inhibitor <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> as enhanced proliferation was accompanied by increased histone acetylation, whereas it elicited changes in culture in cell\u2010cycle regulators, including cyclin D1 and E, and cyclin\u2010dependent kinase (CDK) inhibitors, p21 and p27. Collectively, these data suggest clinically relevant VPA exposures stimulate glial precursor proliferation, though at higher doses can elicit inhibition through differential regulation of CDK inhibitors. Because changes in glial cell functions are proposed as mechanisms contributing to neuropsychiatric disorders, these observations suggest that VPA teratogenic actions may be mediated through changes in astrocyte generation during development. \u00a9 2015 Wiley Periodicals, Inc. 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