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

Abstract

BackgroundExplosive 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.MethodsBasal 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.ResultsThe 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.ConclusionsOverreactive 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.

Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats

“…Our results corroborate the findings of previous studies showing that microglial density peaks brain-wide at P14 and the hippocampus, specifically, at P15 in mice (Kim et al, 2015; Nikodemova et al, 2015). Our data provides novel insight into the normal developmental time course of microglial colonization of the prefrontal cortex and amygdala across the early to mid-postnatal period, which has not previously been examined closely.…”

“…Microglia colonize the rodent brain beginning on embryonic day 9.5 and reach peak numbers by the third postnatal week (Ginhoux et al, 2010; Kim et al, 2015; Nikodemova et al, 2015). They release a variety of diffusible factors, such as chemokines and cytokines, and express a variety of receptors that allow them to respond to and modulate events under normal and abnormal circumstances in the brain.…”

Confounding effect of EEG implantation surgery: Inadequacy of surgical control in a two hit model of temporal lobe epilepsy

“…Microglia counts are highest around P14, begin to decline around P21, and reach adult levels around 6 weeks [11, 15]. The P14 peak has been associated with increased seizure susceptibility [11]. In our study, FS and KA-SZ coincided with high microglia levels, therefore a similar experiment with adult rodents may find a weaker microglia response to electrode-implantation.…”

“…Microglia number and functionality change throughout development and throughout the immune response to injury. Microglia counts are highest around P14, begin to decline around P21, and reach adult levels around 6 weeks [11, 15]. The P14 peak has been associated with increased seizure susceptibility [11].…”

Epileptic Encephalopathy in Infants and Children

“…Microglia are immune cells present in the brain that become activated rapidly with a brain injury such as seizure. Postnatal development of microglia correlates closely with seizure susceptibility (26). In addition, blood-brain barrier compromise allows components of the peripheral immune system to enter the brain.…”