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Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing
Raghavendra Rao1,2, Motaz Nashawaty1, Saher Fatima1
1Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Insights
Hyperglycemia in newborn rats alters hippocampal energy metabolism and dendritic structure, potentially explaining long-term cognitive deficits in extremely low gestational age newborns.
Area of Science:
- Neuroscience
- Neonatal Research
- Metabolic Disorders
Background:
- Hyperglycemia is common in extremely low gestational age newborns (ELGANs) and increases brain injury risk.
- Long-term effects of neonatal hyperglycemia on the developing brain, particularly the hippocampus, are not well understood.
- Adult rat studies show hyperglycemia impacts hippocampal energy metabolism.
Purpose of the Study:
- To investigate the effects of hyperglycemia on the developing hippocampus in rat pups.
- To determine neurochemical and structural changes in the hippocampus following induced hyperglycemia.
- To explore potential mechanisms linking neonatal hyperglycemia to long-term cognitive deficits.
Main Methods:
- Experiment 1: Induced recurrent hyperglycemia (moderate and severe) in rat pups (postnatal days 3-12), assessing hippocampal neurochemistry (1H MR spectroscopy) and dendritic structure (MAP-2 immunohistochemistry) on postnatal day 30.
- Experiment 2: Induced continuous hyperglycemia (postnatal days 2-6) using streptozotocin, analyzing hippocampal mRNA expression of key metabolic and transport genes (Gys1, Ldh, Glut1, Glut3, Mct1, Mct2, Mct4) on postnatal day 6.
Main Results:
- Severe hyperglycemia reduced hippocampal lactate and glutamate/glutamine ratios, while both moderate and severe hyperglycemia increased phosphocreatine/creatine ratios.
- Hyperglycemia led to abnormal synaptic efficacy, indicated by longer apical dendrite segments in the CA1 region.
- Gene expression analysis revealed altered expression of glucose transporters (Glut1, Mct1, Mct4) and glycogen synthesis (Gys1) in hyperglycemic pups.
Conclusions:
- Neonatal hyperglycemia significantly alters hippocampal energy metabolism, substrate transport, and dendrite development in developing rats.
- These neurochemical and structural changes may underlie the hippocampus-mediated cognitive deficits observed in human ELGANs with neonatal hyperglycemia.
- The study provides a preclinical basis for understanding the long-term neurological consequences of hyperglycemia in preterm infants.
Abstract:
Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo 1 H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule-associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs.
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