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.
Methodology/principal findings: 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/significance: Excess glutamatergic signaling in the prenatal stage compromises early brain development via overstimulation of NMDARs.