A postnatal peak in microglial development in the mouse hippocampus is correlated with heightened sensitivity to seizure triggers

• Published in: Brain and behavior 2015-12, Vol.5 (12), p.e00403-n/a
• Main Authors: Kim, Iris, Mlsna, Lauren M., Yoon, Stella, Le, Brandy, Yu, Songtao, Xu, Dan, Koh, Sookyong
• Format: Article
• Language: English
• Subjects: Age; Animals; Brain research; Convulsions & seizures; CX3C Chemokine Receptor 1; Disease Models, Animal; Disease Susceptibility - physiopathology; Early life; Epilepsy; febrile seizures; Fever; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hippocampus - growth & development; Hippocampus - pathology; Hippocampus - physiopathology; Hot Temperature; Hyperthermia; Immune system; Interleukin-1beta - metabolism; Kainic Acid; Laboratory animals; Lipopolysaccharides; Mice, Transgenic; Microglia - pathology; Microglia - physiology; Neuroimmunomodulation - physiology; Nitric Oxide Synthase Type II - metabolism; Original Research; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; RNA, Messenger - metabolism; Seizures, Febrile - pathology; Seizures, Febrile - physiopathology; status epilepticus; Status Epilepticus - pathology; Status Epilepticus - physiopathology; Stem cells; Synapses; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2162-3279; 2162-3279
• DOI: 10.1002/brb3.403

Background Explosive synaptogenesis and synaptic pruning occur in the hippocampus during the first two weeks of postnatal life, coincident with a heightened susceptibility to seizures in rodents. To determine the temporal correlation between microglial development and age‐dependent susceptibility and response to seizures, we quantified developmental changes in basal microglia levels and seizure‐induced microglial activation in the hippocampus of Cx3Cr1GFP/+ transgenic mice. Methods Basal levels of microglia were quantified in the hippocampi of Cx3Cr1GFP /+ mice at P0, P5, P10, P15, P20, P25, P30, P40, and P60. Seizure susceptibility and seizure‐induced microglial activation were assessed in response to febrile seizures (lipopolysaccharide followed by hyperthermia) and kainic acid‐induced status epilepticus. Results The density of microglia within the hippocampus increased rapidly after birth, reaching a peak during the second week of life – the age at which the animals became most vulnerable to seizure triggers. In addition, this peak of microglial development and seizure vulnerability during the second postnatal week represented the time of maximal seizure‐induced microglia activation. Conclusions Overreactive innate immunity mediated by activated microglia may exacerbate acute injury to neuronal synapses and contribute to the long‐term epileptogenic effects of early‐life seizures. Anti‐inflammatory therapy targeting excessive production of inflammatory mediators by activated microglia, therefore, may be an effective age‐specific therapeutic strategy to minimize neuronal dysfunction and prevent increases in susceptibility to subsequent seizures in developing animals. Basal levels of microglia were quantified in the hippocampi of Cx3Cr1GFP /+ mice at P0, P5, P10, P15, P20, P25, P30, P40, and P60. Seizure susceptibility and seizure‐induced microglial activation were assessed in response to febrile seizures (lipopolysaccharide followed by hyperthermia) and kainic acid‐induced status epilepticus. A peak of microglial development and seizure vulnerability during the second postnatal week represented the time of maximal seizure‐induced microglia activation.