title: Prenatal NMDA receptor antagonism impaired proliferation of neuronal progenitor, leading to fewer glutamatergic neurons in the prefrontal cortex.
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.
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Toriumi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.forename: Shiho
authors.initials: S
authors.lastname: Narusawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ikawa
authors.forename: Lingling
authors.initials: L
authors.lastname: Lu
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001526:Behavioral Symptoms / Q000139:chemically induced; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D042282:Microdissection; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010622:Phencyclidine / Q000009:adverse effects*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology* / Q000503:physiopathology; D013550:Swimming / Q000523:psychology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid; D001973:Bromodeoxyuridine; D010622:Phencyclidine