Increased Excitability and Heightened Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses in a Mouse Model of Neonatal Hyperoxia Exposure.

Manimaran Ramani,Lori L Mcmahon,Namasivayam Ambalavanan,Kiara Miller

doi:10.3389/fnsyn.2020.609903

Manimaran Ramani, Lori L Mcmahon + Show 2 more

Open Access

https://doi.org/10.3389/fnsyn.2020.609903

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Abstract

Preterm infants exposed to supraphysiological oxygen (hyperoxia) during the neonatal period have hippocampal atrophy and cognitive dysfunction later in childhood and as adolescents. Previously, we reported that 14-week-old adult mice exposed to hyperoxia as newborns had spatial memory deficits and hippocampal shrinkage, findings that mirror those of human adolescents who were born preterm. The area CA1 region of the hippocampus that is crucial for spatial learning and memory is highly vulnerable to oxidative stress. In this study, we investigated the long-term impact of neonatal hyperoxia exposure on hippocampal CA3–CA1 synaptic function. Male and female C57BL/6J mouse pups were continuously exposed to either 85% normobaric oxygen or air between postnatal days 2–14. Hippocampal slice electrophysiology at CA3–CA1 synapses was then performed at 14 weeks of age. We observed that hyperoxia exposed mice have heightened strength of basal synaptic transmission measured in input-output curves, increased fiber volley amplitude indicating increased axonal excitability, and heightened LTP magnitude at CA3–CA1 synapses, likely a consequence of increased postsynaptic depolarization during tetanus. These data demonstrate that supraphysiological oxygen exposure during the critical neonatal developmental period leads to pathologically heightened CA3–CA1 synaptic function during early adulthood which may contribute to hippocampal shrinkage and learning and memory deficits we previously reported. Furthermore, these results will help shed light on the consequences of hyperoxia exposure on the development of hippocampal synaptic circuit abnormalities that could be contributing to cognitive deficits in children born preterm.

Highlights

Children and adolescents who were born very preterm are at higher risk of a lower intelligence quotient (Brydges et al, 2018) and deficits in executive function and processing speed (Lundequist et al, 2015; Brydges et al, 2018)
These data are consistent with the interpretation that the CA1 dendrites in young adult mice exposed to hyperoxia during the neonatal period are hyperexcitable, perhaps a consequence of increased presynaptic excitability (Figure 1B) compared to air-exposed young adult mice. This is the first preclinical study to investigate the consequence of early life hyperoxia exposure, a condition experienced by preterm infants, on hippocampal synaptic function and long-term plasticity
Using acute brain slice electrophysiology in 14-weekold mice, we discovered that exposure to supraphysiological levels of O2 during the first two postnatal weeks leads to heightened presynaptic excitability, increased strength of basal synaptic transmission, and a greater magnitude of long-term potentiation (LTP) at CA3–CA1 synapses

Summary

Introduction

Children and adolescents who were born very preterm are at higher risk of a lower intelligence quotient (Brydges et al, 2018) and deficits in executive function and processing speed (Lundequist et al, 2015; Brydges et al, 2018). They are at high risk for developing attention deficit hyperactivity disorder and autism spectrum disorder (Rommel et al, 2017; Franz et al, 2018) than their counterparts who were born at term. Though cumulative OS has been linked with neurodegenerative disorders such as Alzheimer’s disease (Cioffi et al, 2019) and Parkinson’s disease (Crotty et al, 2017), the impact of OS during the critical developmental period on brain development and function later in life is not well known

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