In vivo magnetic resonance studies reveal neuroanatomical and neurochemical abnormalities in the serine racemase knockout mouse model of schizophrenia.

Abstract

BACKGROUND:

Decreased availability of the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine is thought to promote NMDAR hypofunction and contribute to the pathophysiology of schizophrenia, including neuroanatomical abnormalities, such as cortical atrophy and ventricular enlargement, and neurochemical abnormalities, such as aberrant glutamate and γ-aminobutyric acid (GABA) signaling. It is thought that these abnormalities directly relate to the negative symptoms and cognitive impairments that are hallmarks of the disorder. Because of the genetic complexity of schizophrenia, animal models of the disorder are extremely valuable for the study of genetically predisposing factors. Our laboratory developed a transgenic mouse model lacking serine racemase (SR), the synthetic enzyme of d-serine, polymorphisms of which are associated with schizophrenia. Null mutants (SR-/-) exhibit NMDAR hypofunction and cognitive impairments. We used 9.4 T magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to compare in vivo brain structure and neurochemistry in wildtype (WT) and SR-/- mice.

METHODS:

Mice were anesthetized with isoflurane for MRI and MRS scans.

RESULTS:

Compared to WT controls, SR-/- mice exhibited 23% larger ventricular volumes (p<0.05). Additionally, in a medial frontal cortex voxel (15 μl), SR-/- mice exhibited significantly higher glutamate/water (12%, t=1.83, p<0.05) and GABA/water (72%, t=4.10, p<0.001) ratios.

CONCLUSIONS:

Collectively, these data demonstrate in vivo neuroanatomical and neurochemical abnormalities in the SR-/- mouse comparable to those previously reported in humans with schizophrenia.

• Authors: Matthew D Puhl, Dionyssios Mintzopoulos, J Eric Jensen, Timothy E Gillis, Glenn T Konopaske, Marc J Kaufman, Joseph T Coyle
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 73 Pg. 269-74 (Jan 2015) ISSN: 1095-953X [Electronic] United States
• PMID: 25461193 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, N-Methyl-D-Aspartate
• Racemases and Epimerases
• serine racemase

Topics

• Animals
• Behavior, Animal
• Brain (metabolism, pathology)
• Cognition Disorders (metabolism)
• Disease Models, Animal
• Magnetic Resonance Imaging (methods)
• Magnetic Resonance Spectroscopy (methods)
• Male
• Mice
• Mice, Transgenic
• Racemases and Epimerases
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Schizophrenia (metabolism, pathology)