TY - JOUR
T1 - Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus
AU - Tran, Phu V.
AU - Fretham, Stephanie J.B.
AU - Wobken, Jane
AU - Miller, Bradley S.
AU - Georgieff, Michael K.
PY - 2012/2
Y1 - 2012/2
N2 - Gestationalneonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1α expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuronspecific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-IIdependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period.
AB - Gestationalneonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1α expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuronspecific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-IIdependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period.
KW - Extracellular signal- regulated kinase
KW - Hippocampal development
KW - Insulin receptor
KW - Insulin-like growth factor I receptor
KW - Micronutrient deficiency
KW - Neurogenesis
KW - Protein kinase B
UR - http://www.scopus.com/inward/record.url?scp=84856199026&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856199026&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00369.2011
DO - 10.1152/ajpendo.00369.2011
M3 - Article
C2 - 22068601
AN - SCOPUS:84856199026
SN - 0193-1849
VL - 302
SP - 316
EP - 324
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 3
ER -