Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice.
Neuroinflammatory conditions such as traumatic brain injury, aging, Alzheimer's disease, and Down syndrome are often associated with cognitive dysfunction. Much research has targeted inflammation as a causative mediator of these deficits, although the diverse cellular and molecular changes that accompany these disorders obscure the link between inflammation and impaired memory. Therefore, we used a transgenic mouse model with a dormant human IL-1beta excisional activation transgene to direct overexpression of IL-1beta with temporal and regional control. Two weeks of hippocampal IL-1beta overexpression impaired long-term contextual and spatial memory in both male and female mice, while hippocampal-independent and short-term memory remained intact. Human IL-1beta overexpression activated glia, elevated murine IL-1beta protein and PGE(2) levels, and increased pro-inflammatory cytokine and chemokine mRNAs specifically within the hippocampus, while having no detectable effect on inflammatory mRNAs in the liver. Sustained neuroinflammation also reduced basal and conditioning-induced levels of the plasticity-related gene Arc.
Hein
Amy M
AM
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Stasko
Melissa R
MR
Matousek
Sarah B
SB
Scott-McKean
Jonah J
JJ
Maier
Steven F
SF
Olschowka
John A
JA
Costa
Alberto C S
AC
O'Banion
M Kerry
MK
D000161:Acoustic Stimulation; D000818:Animals; D003213:Conditioning, Psychological; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D005239:Fear / Q000523:psychology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000276:immunology; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D011939:Mental Recall / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013028:Space Perception / Q000502:physiology*; D014765:Viral Vaccines / Q000276:immunology
D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D014765:Viral Vaccines; C092069:activity regulated cytoskeletal-associated protein; D015232:Dinoprostone