Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat.
Valproic acid (VPA) is a neurotherapeutic drug prescribed for seizures, bipolar disorder, and migraine, including women of reproductive age. VPA is a well-known 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 in vivo models using frontal cerebral cortex of postnatal day (P2) rat. In vitro, VPA exposure elicited dose-dependent, biphasic effects on DNA synthesis and proliferation. In vivo VPA (300 mg/kg) exposure from P2 to P4 increased both DNA synthesis and cell proliferation, affecting primarily astrocyte precursors, as >75% of mitotic cells expressed brain lipid-binding protein. Significantly, the consequence of early VPA exposure was increased astrocytes, as both S100-β+ cells and glial fibrillary acidic protein were increased in adolescent brain. Molecularly, VPA served as an HDAC inhibitor in vitro and in vivo as enhanced proliferation was accompanied by increased histone acetylation, whereas it elicited changes in culture in cell-cycle regulators, including cyclin D1 and E, and cyclin-dependent 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. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 780-798, 2016.
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey.|Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
Hee Jae
HJ
Lee
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey.
Cheryl
C
Dreyfus
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey.|Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, New Jersey.
Emanuel
E
DiCicco-Bloom
D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D005625:Frontal Lobe / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid
astrocyte; cell proliferation; cerebral cortex; cyclin D1; cyclin E; glial precursor; p21; p27; valproic acid