[Abstract Title]. - Society for Neuroscience

constitutive genetic perturbation of NMDA receptor function through the glycine site modulators
D-serine and glycine can result in changes in the GABA system. We and colleagues have
established two mouse genetic models of altered NMDAR modulation: Serine racemase exon 1
knockout (SR-/-) mice have a > 80% reduction in cortical D-serine, resulting in decreased
occupancy of the glycine modulatory site (GMS) and decreased NMDAR-mediated
glutamatergic activity. Mice heterozygous for a null mutation of glycine transporter 1 (GlyT1+/-
mice) exhibit increased occupancy of the NMDA receptor glycine modulatory site. In the present
study, we have investigated the expression of GABAergic markers in SR-/- and Glyt1+/- mice
using a combination of quantitative PCR, western blotting, and immunohistochemical
techniques. Here, we report significant reduction in the expression of PSD-95, PV and glutamate
decarboxylase (GAD67) in the hippocampus of SR-/- mice. In contrast, GlyT1+/- mice exhibit
an increased expression of PSD-95 and PV in the hippocampus. Preliminary
immunohistochemical investigations demonstrate a reduction in the number of GAD67-postive
neurons the prefrontal cortex (pre- and infralimbic cortices) and all areas of the hippocampus in
SR -/- mice. Thus, we demonstrate that genetic manipulation of the availability of GMS ligands
can influence the expression of GABAergic markers in either direction. These results are
consistent with the hypothesis that the NMDARs on the PV-positive GABAergic interneurons
are the subset of NMDA receptors critical to the pathophysiology of schizophrenia.
Disclosures: M.A. Benneyworth, None; A.C. Basu , None; J.T. Coyle, Patent relating to the
use of d-serine in the treatment of neuropsychiatric disorders. Patent is held by McLean Hospital
and JTC., E. Ownership Interest (stock, stock options, patent or other intellectual property); K.
Suzuki, None.
Poster
254. Schizophrenia: Mutant Animal Models
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 254.4/X21
Topic: C.15.d. Schizophrenia: Mutant animal models
Title: Loss of glutamate transporter GLAST (EAAT1) causes 'schizophrenia-like' phenotype in
mice
Authors: *R.-M. KARLSSON 1 , M. HEILIG 1 , A. HOLMES 2 ;
1 NIH, Bethesda, MD; 2 NIH, Rockville, MD
Abstract: Glutamatergic dysfunction is increasingly implicated in the pathophysiology of
schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlies
many of the symptoms in schizophrenia. However, the mechanisms involved are not well