![]() These mice were maintained on a C57BL/6 background and were used for all experiments. Adult male and female SRKO (−/−) mice and their wild type (WT) littermates were bred in-house from heterozygote SR (+/−) breeding pairs. SRKO mice were originally generated as described 18. The presence of these deficits may help us understand their underlying mechanisms and relationships to long term NMDAR dysfunction. We hypothesized that SRKO mice will demonstrate impairments in translationally-relevant EEG biomarkers that are consistent with deficits associated with schizophrenia. This well-established model exhibits a wide range of schizophrenia-like phenotypes 18, 19, 20, 21 and exhibit enhanced oxidative damage and decreased parvalbumin immunoreactivity 22. These mice lack expression of the enzyme responsible for synthesis of D-serine, a co-agonist at the NMDAR, and consequently exhibit chronic NMDAR hypofunction 18. Here we have examined the relationship between EEG biomarker activity and chronic NMDAR hypofunction by utilizing the serine racemase knockout (SRKO) mouse model. Recent genome-wide association studies have identified a number of genetic risk factors for schizophrenia associated with glutamatergic signaling, including the SRR gene which encodes serine racemase 16, 17. Understanding the underlying mechanisms of EEG biomarkers could aid development of new targeted therapies that aim to alleviate cognitive deficits in patients with psychosis 15. Antipsychotic treatment can counteract NMDA antagonist-induced changes in some EEG biomarkers, though their therapeutic mechanism is somewhat unclear 14. Indeed, patients with schizophrenia have well documented impairments in fast-spiking GABAergic interneurons, which may arise from these neurons’ increased susceptibility to oxidative damage 12, 13. These drugs also induce oxidative damage within cortical circuitry 11, potentially disrupting excitatory / inhibitory (E/I) balance and causing downstream abnormalities in gamma band oscillations and cognition. NMDAR antagonists can transiently recapitulate positive, negative, and cognitive symptoms of schizophrenia in healthy subjects and animal models 8, 9, including deficits in EEG biomarkers like the ASSR 10. Additionally, neural activity abnormalities have been reported in the gamma frequency range (30–80 Hz), either at rest or during cognitive and sensory related task performance 1.Ĭonverging evidence suggests chronic NMDA receptor (NMDAR) hypofunction is central to the pathophysiology of schizophrenia and related psychiatric disorders 6, 7. Of particular interest are disturbances in sensory gating and entrainment to 40 Hz auditory stimuli (auditory steady state response ASSR), which are impaired in patients with schizophrenia and individuals at high risk to transition to psychosis 5. A number of electroencephalographic (EEG) biomarkers are associated with impaired cognitive flexibility, attention, executive functioning, and social behavior 3, 4. Importantly, our gamma band findings suggest an aberrant signal-to-noise ratio impairing cognition that occurs with NMDAR hypofunction, potentially tied to impaired task-dependent alteration in functional connectivity.Ībnormalities in neural network activity are common across a range of psychiatric disorders and may provide a diagnostic means for early diagnosis 1, 2. In conclusion, SRKO mice demonstrate how chronic NMDAR hypofunction contributes to deficits in certain translationally-relevant EEG biomarkers altered in schizophrenia. However, other biomarkers including the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. Additionally, SRKO mice exhibited sensory gating impairments in both evoked-gamma power and event-related potential amplitude. SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition and enhanced background (pre-investigation) gamma activity. We utilized in vivo EEG recordings and behavioral analyses to perform a battery of electrophysiological biomarkers in an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice, and their wild-type littermates. Thus, characterizing these biomarkers is of significant interest for early diagnosis of schizophrenia and development of novel treatments. Converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role in the pathophysiology of schizophrenia and likely contributes to biomarker impairments. ![]() 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.
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