The effect of Human Mutant APP/PS1 Transgenes on Cognitive and Executive Function in a Mouse Model of Neonatal Hypoxia-Ischemia

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ESPR419
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Background: Hypoxic-Ischemic Encephalopathy (HIE) alters cerebral function development. Despite the use of therapeutic hypothermia, HIE survivors have executive dysfunction similar to adults with neurodegeneration, which is understudied in HI models.  More discriminatory testing will improve sensitivity of cognitive testing. Mice expressing transgenes for many adult onset neurodegenerative diseases have higher mortality after early brain injury. We examine cognitive and executive function after surviving neonatal HI.

Objective: To test the hypotheses that neonatal HI in mice results in adult cognitive impairments, which is worse in mice expressing human familial Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilin-1 (PS1).

Methods: APP/PS1 transgenic (Tg) mice, and non-transgenic (nTg) littermates received neonatal HI (carotid ligation/ 45m of FiO2 0.08) or anesthesia alone (sham) at P10. We tested all available mice: reflexes from P11-21 and executive functions using light/dark box, open field, Y-maze from P30-61, and visual discrimination (VD) and Reversal Learning (RL) in touchscreen testing after P61. Data from 35 Tg and 30 nTg mice were analyzed using non-parametric methods (SPSSv24).

Results: Survival at P60 was unaffected by genotype. HI mice (n=43, nTg and Tg) have slower weight gain after P18 (p=0.04), delayed extinction of cliff aversion (p=0.004) and negative geotaxis (p=0.002), as well as earlier emergence and extinction of air righting (p=0.01) vs. sham. Tg mice trended toward more time in the dark and spend less center-time in open field (p=0.06). HI-Tg mice trended toward delayed emergence of forelimb grasp, eye opening and some failed audio startle by P21. HI-Tg mice had less spontaneous alternations (p=0.006 vs. sham-Tg) in Y-maze.  All HI mice show a trend toward fewer mean correct responses and impaired VD. HI-Tg mice required more sessions to pass VD than non-Tg (p=0.05), and no HI-Tg mice passed RL in touchscreen testing. 

Conclusion: This is the first study of developmental cognitive function after neonatal HI in familial AD mice. Weight gain and reflex abnormalities confirm previous findings in neonatal HI. VD is now being reported following neonatal HI. Differences between HI nTg and Tg mice confirms VD usefulness in discriminating learning deficits.  Genetic background may modulate late learning outcomes after neonatal HI.  Further studies about learning acquisition, cognitive flexibility and executive dysfunction will provide insights into long-term effects of HIE in neonates of different genetic backgrounds.

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Johns Hopkins University
Johns Hopkins University School of Medicine
Johns Hopkins
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University

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