title: Overstimulation of NMDA receptors impairs early brain development in vivo.
abstract: BACKGROUND
  Brains of patients with schizophrenia show both neurodevelopmental and functional deficits that suggest aberrant glutamate neurotransmission. Evidence from both genetic and pharmacological studies suggests that glutamatergic dysfunction, particularly with involvement of NMDARs, plays a critical role in the pathophysiology of schizophrenia. However, how prenatal disturbance of NMDARs leads to schizophrenia-associated developmental defects is largely unknown.
  
  
  RESULTS
  Glutamate transporter GLAST/GLT1 double-knockout (DKO) mice carrying the NMDA receptor 1 subunit (NR1)-null mutation were generated. Bouin-fixed and paraffin-embedded embryonic day 16.5 coronal brain sections were stained with hematoxylin, anti-microtubule-associated protein 2 (MAP2), and anti-L1 antibodies to visualize cortical, hippocampal, and olfactory bulb laminar structure, subplate neurons, and axonal projections. NR1 deletion in DKO mice almost completely rescued multiple brain defects including cortical, hippocampal, and olfactory bulb disorganization and defective corticothalamic and thalamocortical axonal projections.
  
  
  CONCLUSIONS
  Excess glutamatergic signaling in the prenatal stage compromises early brain development via overstimulation of NMDARs.
authors.affiliation: Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Aida
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Ito
authors.forename: Yuko K
authors.initials: YK
authors.lastname: Takahashi
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D027341:Excitatory Amino Acid Transporter 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009830:Olfactory Bulb / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C493396:Slc1a2 protein, mouse; C493393:Slc1a3 protein, mouse