Abstract
N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.
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Acknowledgements
We thank Dr Furukawa H for synthesizing PCP. This study was supported by Grants-in-aid for Scientific Research (A) (22248033), Scientific Research (B) (20390073) (21390045) and Exploratory Research from the JSPS (19659017) (22659213); by the ‘Academic Frontier’ Project for Private Universities (2007–2011) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); by Regional Joint Research Program supported by grants to Private Universities to Cover Current Expenses from MEXT; by Research on Regulatory Science of Pharmaceuticals and Medical Devices from the Ministry of Health, Labour and Welfare, Japan (MHLW); by Research on Risk of Chemical Substances, Health and Labour Science Research Grants supported by MHLW; and by the joint research project under the Japan-Korea basic scientific cooperation program (JSPS).
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Toriumi, K., Mouri, A., Narusawa, S. et al. Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex. Neuropsychopharmacol 37, 1387–1396 (2012). https://doi.org/10.1038/npp.2011.324
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DOI: https://doi.org/10.1038/npp.2011.324
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