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.

Nyckelord

Adrenocorticotropic Hormone/blood

Aging/metabolism/psychology

Animals

Apoptosis/drug effects

Astrocytes/pathology

Blotting

Western

Body Weight/physiology

Caspase 3

Caspases/metabolism

DNA

Complementary/biosynthesis/genetics

Female

Glial Fibrillary Acidic Protein/metabolism

Gliosis/chemically induced/pathology

Hippocampus/*pathology

Hydrocortisone/blood

Immunohistochemistry

Inflammation/*pathology

Interleukin-6/*pharmacology

Maze Learning/*physiology

Nerve Degeneration/*pathology

Pregnancy

Prenatal Exposure Delayed Effects

Rats

Rats

Wistar

Receptors

GABA-A/*physiology

Receptors

N-Methyl-D-Aspartate/drug effects/*physiology

Reverse Transcriptase Polymerase Chain Reaction

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