Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimer's disease.
Alzheimer's disease is associated with cognitive decline and seizures. Growing evidence indicates that 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 with high levels of amyloid beta (Aβ). These mice develop generalized epileptiform activity, including nonconvulsive seizures, consistent with alterations in corticothalamic network activity. Amyloid precursor protein mice exhibited reduced activity marker expression in the reticular thalamic nucleus, 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 the reticular thalamic nucleus that may contribute to corticothalamic dysfunction. These results are consistent with our findings of impaired sleep maintenance in amyloid precursor protein 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 Alzheimer's disease.
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Anupam
A
Hazra
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Brian F
BF
Corbett
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Jason C
JC
You
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Suzan
S
Aschmies
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Lijuan
L
Zhao
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Ke
K
Li
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.
Angelo C
AC
Lepore
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Eric D
ED
Marsh
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107.|Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107.|Memory & Brain Research Center, Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.
Jeannie
J
Chin
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001519:Behavior; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000503:physiopathology*; D003071:Cognition; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D009415:Nerve Net / Q000503:physiopathology*; D012892:Sleep Deprivation; D013787:Thalamic Nuclei / Q000503:physiopathology*
D016229:Amyloid beta-Peptides
Alzheimer's disease; Amyloid precursor protein; Corticothalamic; Epilepsy; Reticular thalamic nucleus (nRT); Seizure; Sleep fragmentation