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Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling.

Alzheimer’s disease (AD) has been associated with increased phosphorylation of the translation initiation factor 2α(eIF2α) at serine 51. Increased phosphorylation of eIF2αalters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2αindeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with aneIF2αS51Aknock-in line that expresses the nonphosphorylatable eIF2αvarianteIF2αS51A. Behavioral assessment of the resulting mice revealed motor and cognitive deficits in 5xFAD mice that were, with the possible exception of locomotor hyperactivity, not restored by theeIF2αS51Aallele. Telemetric intracranial EEG recordings revealed no measurable effects of theeIF2αS51Aallele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by theeIF2αS51Aallele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2αin the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2αlevels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2αto emerge; they also show that heterozygosity for the nonphosphorylatableeIF2αS51Aallele has limited effects on 5xFAD-related disease manifestations.