Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimers disease

摘要

Alzheimer's disease (AD) is associated with cognitive decline as well as seizures. Growing evidence indicates seizures contribute to cognitive deficits early in disease, but how they develop and impact cognition are unclear. To investigate potential mechanisms, we studied a mouse model that overexpresses mutant human amyloid precursor protein (APP) with high levels of Aβ. These mice develop generalized epileptiform activity, including nonconvulsive seizures, consistent with alterations in corticothalamic network activity. APP mice exhibited reduced activity marker expression in the reticular thalamic nucleus (nRT), a key inhibitory regulatory nucleus, and increased activity marker expression in downstream thalamic relay targets that project to cortex and limbic structures. Slice recordings revealed impaired cortical inputs to nRT that may contribute to corticothalamic dysfunction. These results are consistent with our findings of impaired sleep maintenance in APP mice. Finally, the severity of sleep impairments predicted the severity of deficits in Morris water maze, suggesting corticothalamic dysfunction may relate to hippocampal dysfunction, and may be a pathophysiological mechanism underlying multiple behavioral and cognitive alterations in AD.