Calcium/calmodulin-dependent protein kinase IIα heterozygous knockout mice show electroencephalogram and behavioral changes characteristic of a subpopulation of schizophrenia and intellectual impairment

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKII alpha heterozygous mouse (CaMKII alpha-hKO). The current study characterizes behavioral phenotypes of CaMKII alpha-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKII alpha-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKII alpha-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKII alpha-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKII alpha-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2+ channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKII alpha-hKO mice likely model a subpopulation of patients with schizophrenia. (C) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

In this study, the behavioral phenotypes and neurophysiological profile of CaMKII alpha-hKO mice were characterized. These mice displayed hypoactivity, less anxiety-like behavior, and severe cognitive dysfunction. EEG recording revealed altered event-related potentials and increased power in theta range time-frequency measures. The findings suggest that CaMKII alpha-hKO mice may model a subpopulation of schizophrenia patients.