Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population

Robert E Featherstone; Rick Shin; Jeffrey H Kogan; Yuling Liang; Mitsuyuki Matsumoto; Steven J Siegel

doi:10.1016/j.nbd.2014.10.010

Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population

Neurobiol Dis. 2015 Jan:73:289-95. doi: 10.1016/j.nbd.2014.10.010. Epub 2014 Oct 22.

Authors

Robert E Featherstone¹, Rick Shin², Jeffrey H Kogan², Yuling Liang¹, Mitsuyuki Matsumoto², Steven J Siegel³

Affiliations

¹ Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
² Translational Psychiatry, CNS - Astellas Research Institute of America LLC, Skokie, IL, USA.
³ Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: siegels@upenn.edu.

PMID: 25461194
DOI: 10.1016/j.nbd.2014.10.010

Abstract

Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia.

Keywords: EEG; Mismatch negativity; Mouse; NMDA; Schizophrenia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / physiopathology*
Disease Models, Animal
Evoked Potentials / physiology*
Gamma Rhythm / physiology*
Genetic Predisposition to Disease
Mice
Mice, Inbred C57BL
Mice, Knockout
Prodromal Symptoms
Receptors, N-Methyl-D-Aspartate / metabolism*
Schizophrenia / physiopathology*
Social Isolation*

Substances

NR1 NMDA receptor
Receptors, N-Methyl-D-Aspartate

Grants and funding

5R01DA023210-02/DA/NIDA NIH HHS/United States