A novel model for prenatal brain damage. II. Long-term deficits in hippocampal cell number and hippocampal-dependent behavior following neonatal GABAA receptor activation.
Premature infants are at especially high risk for asphyxia, seizures, and other conditions that cause hypoxia-ischemia. These events result in abnormal brain pathology and behavioral deficits that persist throughout adolescence and into adulthood. Current rodent models of human infant hypoxic-ischemic brain damage have focused on exogenous glutamate receptor agonist exposure in the postnatal day 7 rat. While this model is considered analogous to the newborn human, no adequate models for preterm infant brain damage have been developed. Recent work from our lab has proposed a potential model for preterm infant brain damage in which neonatal rats are treated with exogenous muscimol, the selective gamma-aminobutyric acid(A) (GABA(A)) receptor agonist, on postnatal days 0 and 1. In the companion paper to this one (Exp. Neurol., in press), we report fewer neurons in the hippocampal formation on postnatal day 7 (6 days after treatment), but the persistence of these anatomical deficits, and potential resultant behavioral dysfunctions, were not investigated. In the current experiment, we documented that muscimol exposure on postnatal days 0 and 1 leads to fewer neurons in the male and female rat hippocampus (CA1, CA2/3, and dentate gyrus) on postnatal day 21. Also, neonatal muscimol exposed males and females displayed deficits on hippocampal-dependent learning tasks such as a preweanling version of the Morris water maze task and the open field task. We conclude that exposure to exogenous GABA(A) receptor activation over the first 2 days of postnatal life, a model for preterm infant hypoxic injury, produces anatomical and behavioral deficits observed into adolescence.
Nuñez
Joseph L
JL
Physiology Department, University of Maryland School of Medicine, Baltimore 21201, USA. jnune001@umaryland.edu
Alt
Jesse J
JJ
McCarthy
Margaret M
MM
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001835:Body Weight; D001925:Brain Damage, Chronic / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D002452:Cell Count; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning; D009118:Muscimol; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013037:Spatial Behavior; D013995:Time
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol