Symposium: MMN as a translational biomarker of psychosis: from bench-to-bedside-to-real-world community settings
Thursday, Sep 10, 2015
MMN as a highly sensitive measure of subtle changes in NMDAR-mediated glutamate transmission in mice
Psychiatry, University of Pennsylvania, Philadelphia, United States
Reductions in glutamate function are an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental 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. This presentation describes a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1). NR1+/- mice showed a 30% reduction in NR1 expression and were reared after weaning in either group or isolated conditions. Outcomes include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISI) and deviance-related mismatch negativity (MMN). In contrast to (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potentials (ERPs) including the murine P50 and N100 equivalents, or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in MMN . 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.