Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction

Abstract

Introduction: Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. While the pathophysiology of schizophrenia remains poorly understood, converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role and likely contributes to biomarker impairments. Thus, the characterization of such biomarkers is of significant interest for both the early diagnosis of schizophrenia and the development of novel treatments. Methods: We utilized an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice. In vivo EEG recording and behavioral analyses were performed on adult male and female SRKO mice and wild-type littermates to determine the impact of chronic NMDAR hypofunction on a battery of translationally-relevant electrophysiological biomarkers. Results: SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition. This impairment was associated with enhanced background (pre-investigation) broadband gamma activity that only appeared during social task performance. Additionally, SRKO mice exhibited sensory gating impairments, in both gamma power and event-related potential amplitude. However, other biomarkers such as the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. Conclusions: SRKO mice provide a useful model to understand how chronic NMDAR hypofunction contributes to deficits in a subset of translationally-relevant EEG biomarkers that are altered in schizophrenia. Importantly, our gamma band findings support the hypothesis that an aberrant signal-to-noise ratio impairing cognition occurs with NMDAR hypofunction, which may be tied to impaired task-dependent alteration in functional connectivity.

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

“…Notably, mice lacking the NADH-oxidase-2, an enzyme that produces superoxide, are resilient to perinatal ketamine-induced PV neurons defects [126]. A genetic model of NMDAR hypofunction relevant to schizophrenia, the D-serine racemase KO mouse which show altered neuronal oscillations [127], also have reduced number of prefrontal PV interneurons together with OxS [15], both of which can be prevented by an early-life NAC treatment (coll. with Joe Coyle, unpublished).…”