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Published on: November 20, 2015
Elevated insulin growth factor-1 in dentate gyrus induces cognitive deficits in pre-term newborns
Deep R Sharma1,2, Bokun Cheng1,2, Manoj Kumar Jaiswal3
1Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Insights
Premature birth and NICU stress impair infant learning and memory by disrupting brain development. Insulin growth factor-1 (IGF1) blockade rescues these cognitive deficits and synaptic changes in premature rabbits.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Premature infants experience maternal hormone deprivation and neonatal stress.
- This leads to long-term learning and memory deficits.
- The neonatal intensive care unit (NICU) environment exacerbates these challenges.
Purpose of the Study:
- To investigate how prematurity and neonatal stress affect dentate gyrus (DG) development.
- To identify the role of insulin growth factor-1 (IGF1) in mediating cognitive deficits.
- To explore potential therapeutic strategies for mitigating these effects.
Main Methods:
- Utilized a rabbit model of prematurity and neonatal stress.
- Assessed DG cellularity, neurogenesis, and synaptic structure.
- Analyzed gene expression and serum hormone levels.
- Investigated the effects of IGF-1 receptor blockade on cognitive function and synaptic markers.
Main Results:
- Prematurity and stress altered DG maturation, increasing cell numbers but reducing synaptic density and function.
- Preterm rabbits exhibited cognitive deficits linked to altered gene expression in DG granule cells.
- Elevated IGF1 levels were observed in preterm kits.
- Blocking the IGF-1 receptor ameliorated cognitive deficits and restored synaptic integrity.
Conclusions:
- Neonatal stress and prematurity disrupt DG development and induce cognitive dysfunction.
- IGF1 plays a critical role in mediating these detrimental effects.
- IGF1 inhibition presents a promising therapeutic avenue for rescuing cognitive deficits in premature infants.
Abstract:
Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits and that these effects are mediated by insulin growth factor-1 (IGF1). Nonmaternal care of premature rabbits increased the number of granule cells and interneurons and reduced neurogenesis, suggesting accelerated premature maturation of DG. However, the density of glutamatergic synapses, mature dendritic spines, and synaptic transmission were reduced in preterm kits compared with full-term controls, indicating that premature synaptic maturation was abnormal. These findings were consistent with cognitive deficits observed in premature rabbits and appeared to be driven by transcriptomic changes in the granule cells. Preterm kits displayed reduced weight, elevated serum cortisol and growth hormone, and higher IGF1 expression in the liver and DG relative to full-term controls. Importantly, blocking IGF-1 receptor in premature kits restored cognitive deficits, increased the density of glutamatergic puncta, and rescued NR2B and PSD95 levels in the DG. Hence, IGF1 inhibition alleviates prematurity-induced cognitive dysfunction and synaptic changes in the DG through modulation of NR2B and PSD95. The study identifies a novel strategy to potentially rescue DG maldevelopment and cognitive dysfunction in premature infants under stress in NICUs.
