Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning.
During pregnancy, infection or immune responses induce cytokine release, which might influence fetal neurodevelopment, leading to neurodegenerative disease in adulthood. Because the hippocampus is a key area for learning and memory, we evaluated 4- and 24-wk-old rats for the effects of early and late prenatal exposure to interleukin-6 (IL-6) on hippocampal morphology, expression of mRNA for IL-6, the gamma-aminobutyric acid receptor (GABA(Aalpha5)), the NR1 subunit of the N-methyl-D-aspartate receptor, and glial fibrillary acidic protein (GFAP), caspase-3 protein and mRNA levels, and learning abilities. Late exposure increased serum IL-6 and hippocampal expression of IL-6 mRNA at 4 and 24 wk. All adult rats showed neuronal loss in the hilus and astrogliosis; males had losses mainly in the CA2 and CA3 regions, and females in CA1. Expression of GABA(Aalpha5), NR1, and GFAP mRNA increased in late-exposed males and females at 4 and 24 wk. mRNA and protein levels of the apoptosis marker caspase-3 were increased in all late-exposed rats except males at 4 wk. Evaluation of hippocampus-dependent working memory in the Morris water maze at 20 wk of age showed increases in escape latency and time spent near the pool wall in all IL-6 adult rats, especially females. These findings suggest that fetal IL-6 exposure, especially in late pregnancy, leads to increased IL-6 levels in the circulation and hippocampus, abnormalities of hippocampal structural and morphology, and decreased learning during adulthood.
Samuelsson
Anne-Maj
AM
Cardiovascular Institute and Wallenberg Laboratory, Sahlgrenska Academy, Göteborg Univ., S-413 45 Göteborg, Sweden. anne-maj.samuelsson@wlab.gu.se
Jennische
Eva
E
Hansson
Hans-Arne
HA
Holmäng
Agneta
A
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000375:Aging / Q000378:metabolism / Q000523:psychology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000473:pathology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D006624:Hippocampus / Q000473:pathology*; D006854:Hydrocortisone / Q000097:blood; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000494:pharmacology*; D018782:Maze Learning / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; C409466:NR1 NMDA receptor; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D000324:Adrenocorticotropic Hormone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D006854:Hydrocortisone