The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain

Abstract

Fetuses exposed to an inflammatory environment are predisposed to long‐term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well‐established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba‐1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67‐positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2 hr after LPS treatment, declined at 6 hr and showed overall inhibition at 24 hr. In summary, our study revealed that LPS‐induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.

Dose-related shifts in proteome and function of extracellular vesicles secreted by fetal neural stem cells following chronic alcohol exposure

“…However, there were also significant differences. For example, the dominant pathway overrepresentation with heavy exposure, was the mechanistic target of rapamycin (mTor) cellular response amino acid starvation, an established stress response in animal models of prenatal ethanol exposure [ 90 , 91 ], that is associated with inflammation and fetal brain injury [ 92 ] and disorganized cortical lamination [ 93 ].…”

Decreased level of TREM like Transcript 1 (TLT‐1) is associated with prematurity and promotes the in‐utero inflammatory response to maternal lipopolysaccharide (LPS) exposure

“…We next examined the bodies of pups exposed to LPS via maternal injection. Firstly, because of the potential 40 but complex 41 role of TNF in dysregulation of the fetal brain, and because of data suggesting that amniotic inflammation rapidly generates a signal in this tissue, 40,42,43 we isolated fetal brain and measured RNA expression of TNF. We observed that exposure to LPS, as opposed to PBS, during pregnancy generated increased expression of TNF in the fetal brain of both WT and KO pups by 16 h post injection (Figure 6).…”

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity

“…Maternal inflammation is also known to be a significant risk factor for both ASD and brain overgrowth 19,85,[101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117] . Therefore, one of our initial hypotheses was that the chronically increased brain microglia underlies some or all of the abnormal brain pathology and behaviors in the MIR model as microglia have been demonstrated to influence several related behaviors and mTOR signaling 90,[226][227][228][229][230][231][232] . However, our experiments which ablated microglia in the adult brain suggest that the role of microglia in the etiology of MIR-induced abnormalities is complex.…”