Interleukin-1 mediates long-term hippocampal dentate granule cell loss following postnatal viral infection.
Viral infections of the developing CNS can cause long-term neuropathological sequela through undefined mechanisms. Proinflammatory cytokines such as IL-1beta have gained attention in mediating neurodegeneration in corticohippocampal structures due to a variety of insults in adults, though there is less information on the developing brain. Little is known concerning the spatial-temporal pattern of IL-1beta induction in the developing hippocampus following live virus infection, and there are few studies addressing the long-term consequences of this cytokine induction. We report that infection of rats with lymphocytic choriomeningitis virus on postnatal day 4 induces IL-1beta protein in select regions of the hippocampus on 6, 15, 21, and 45 days after infection. This infection resulted in a 71% reduction of dentate granule cell neurons by the time the rats reached mid-adulthood. We further investigated the causative role of IL-1 in this dentate granule cell loss by blocking IL-1 activity using an IL-1ra-expressing adenoviral vector administered at the time of infection. Blockade of IL-1 abrogated the infection-associated neuron loss in this vivo model. Considering that IL-1 can be triggered by multiple perinatal insults, our findings suggest that early therapy with anti-inflammatory agents that block IL-1 may be effective for reducing adulthood neuropathology.
Orr
Anna G
AG
Department of Psychiatry, Emory University, Atlanta, GA 30322, USA.
Sharma
Anup
A
Binder
Nikolaus B
NB
Miller
Andrew H
AH
Pearce
Bradley D
BD
D000818:Animals; D000831:Animals, Newborn / Q000821:virology*; D018891:Dentate Gyrus / Q000166:cytology / Q000473:pathology / Q000821:virology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008216:Lymphocytic Choriomeningitis / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew
D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta