NYMC Faculty Publications

Elevated Insulin Growth Factor-1 in Dentate Gyrus Induces Cognitive Deficits in Pre-Term Newborns

Deep R. Sharma, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Bokun Cheng, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Manoj Kumar Jaiswal, Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Xusheng Zhang, Computational Genomics Core, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Ajeet Kumar, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Nirzar Parikh, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Divya Singh, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Hardik Sheth, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Merina Varghese, Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Kostantin Dobrenis, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Xiaolei Zhang, Departments of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
Patrick R. Hof, Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Patric K. Stanton, Departments of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
Praveen Ballabh, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Author Type(s)

Faculty

Journal Title

Cerebral Cortex

First Page

6449

Last Page

6464

Document Type

Article

Publication Date

5-9-2023

Department

Cell Biology and Anatomy

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.

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