Hippocampal mTOR Dysregulation and Morphological Changes in Male Rats after Fetal Growth Restriction

Abstract

Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by “sham” operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.

Perspectives on frailty as a total life‐course disease with consideration of the fetal environment

“…33 Krishna et al also reported that a modest association between birth weight and cognitive ability in later life was observed from a systematic review. 34 The detailed mechanism underlying such association between conditions at birth and later life cognitive function remains largely unexplored; however, several possible mechanisms can be proposed: (i) alteration of the prenatal brain environment could rewire the brain structure and impact on later-life cognitive abilities 35 ; (ii) dysregulation of hippocampal cell proliferation and mammalian target of rapamycin (mTOR) signaling was reported by Schomig et al 36 (however, mTOR activation varied in different ways depending on the cause of IUGR); (iii) an earlier life-induced propensity toward diseases such as hypertension or diabetes mellitus may facilitate age-related dementia possibly via vascular dysfunction; and (iv) alteration of IGF-1 level, which was previously associated with dementia risk, particularly for Alzheimer's disease, might be provoked by earlier life abnormalities or IUGR. 33,37 IGF-1 also plays an essential role in skeletal muscle morphogenesis and maturation.…”