High-Frequency Neuronal Oscillatory Abnormalities in the Phospholipase C-β1 Knockout Mouse Model of Schizophrenia

Abstract

Background Schizophrenia is a complex neuropsychiatric disorder characterized by psychoses, socioaffective disturbances, and cognitive deficits. The phosphodiesterase enzyme phospholipase C-β1 has been reported to be reduced in postmortem tissue of schizophrenia patients. Dysregulation of neuronal oscillations, particularly those in the higher frequency range such as beta (12–30 Hz) and gamma (30–80 Hz), are also associated with this disorder. We investigated the influence of phospholipase C-β1 gene deletion on cortical oscillatory activity and sensorimotor gating behavior. Methods Adult phospholipase C-β1 knockout and wild-type C57Bl/6J control mice (total n = 26) underwent surgical implantation of extradural electrodes to allow electrocorticography recordings. Electrocorticography was recorded during prepulse inhibition behavior sessions to measure ongoing and auditory-evoked electrophysiological responses. Mice were also pretreated with antipsychotic drugs haloperidol (0.25 mg/kg), clozapine (2.5 mg/kg), and olanzapine (5 mg/kg). Results Phospholipase C-β1 knockout mice exhibited reduced prepulse inhibition and diminished power and phase synchrony of beta and gamma oscillatory responses to auditory stimuli as well as elevated ongoing beta oscillations. Reductions in prepulse inhibition were highly correlated with the power and phase synchrony of evoked oscillations. Clozapine and olanzapine ameliorated the prepulse inhibition deficit in phospholipase C-β1 knockout mice, but not the electrophysiology abnormalities. Conclusions Phospholipase C-β1 reduction leads to disturbances to beta and gamma oscillatory dynamics and prepulse inhibition behavior. The strong relationships between these measures demonstrate the importance of event-related oscillatory activity to sensorimotor gating behavior. However, dissociation of these measures observed in the drug studies suggests that abnormalities in neuronal networks may not necessarily need to be corrected for behavioral improvement.

The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice

“…Surgical implantation of local field potential (LFP) recording electrodes was performed, as described previously (Hudson et al, 2018), on a subset of the mice used for behaviour following completion of the TUNL testing. Briefly, mice were anesthetised using isoflurane and secured in a digital stereotaxic frame.…”

“…Auditory-evoked oscillatory power. We next examined the gamma oscillatory response to the presented auditory clicks, as previously described (Hudson et al, 2018). Continuous LFP recordings were subjected to a time-frequency analysis around each auditory stimulus (-500 ms to 500 ms relative to onset).…”

Differential Effects of Chronic Methamphetamine Treatment on High-Frequency Oscillations and Responses to Acute Methamphetamine and NMDA Receptor Blockade in Conscious Mice

“…Prior to analysis, EEG was visually inspected to allow for rejection of noise or movement artefacts. From the clean EEG recordings, we performed two analyses which were compared between the groups, as described previously [ 44 , 47 , 48 ]: (1) spontaneous, or ongoing, oscillations in the beta (20–30 Hz) and gamma (30–80 Hz) high-frequency bands; (2) evoked responses triggered by the intermittent acoustic stimuli, incorporating assessment of changes in the power of beta and gamma oscillations triggered by the stimuli, as well as the individual components of the event-related potential (ERP, see Figure 2 ). We only calculated data acquired after injection, and data from left and right hemispheres were averaged.…”

Differential Effects of Chronic Methamphetamine Treatment on High-Frequency Oscillations and Responses to Acute Methamphetamine and NMDA Receptor Blockade in Conscious Mice

“…Prior to analysis, EEG was visually inspected to allow for rejection of noise or movement artefacts. From the clean EEG recordings, we performed two analyses which were compared between the groups, as described previously [44,47,48]: (1) spontaneous, or ongoing, oscillations in the beta (20-30Hz) and gamma (30-80Hz) high-frequency bands; (2) evoked responses triggered by the intermittent acoustic stimuli, incorporating assessment of changes in the power of beta and gamma oscillations triggered by the stimuli, as well as the individual components of the event-related potential (ERP, see figure 2). We only calculated data acquired after injection, and data from left and right hemispheres were averaged.…”