title: 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.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, Belmont, MA 02478, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Puhl
authors.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; McLean Imaging Center, Belmont, MA 02478, USA.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Mintzopoulos
authors.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; McLean Imaging Center, Belmont, MA 02478, USA.
authors.forename: J Eric
authors.initials: JE
authors.lastname: Jensen
authors.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; McLean Imaging Center, Belmont, MA 02478, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Gillis
authors.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, Belmont, MA 02478, USA.
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Konopaske
authors.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; McLean Imaging Center, Belmont, MA 02478, USA.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Kaufman
authors.affiliation: Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA; Harvard Medical School, Department of Psychiatry, McLean Hospital, Boston, MA 02115, USA. Electronic address: joseph_coyle@hms.harvard.edu.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D003072:Cognition Disorders / Q000378:metabolism*; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology*; D000099300:Serine Racemase
chemical_list: D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D000099300:Serine Racemase
keywords: Glutamate; Magnetic resonance imaging; Magnetic resonance spectroscopy; Schizophrenia; Serine racemase knockout mouse; Ventricular volume; γ-Aminobutyric acid