Long-term effects of neonatal single or multiple isoflurane exposures on spatial memory in rats

Abstract

General anesthetics are neurotoxic to neonatal rodents and non-human primates. Neonatal exposure to general anesthetics has been associated with long-term cognitive deficits in animal models. Some data from humans are consistent with long-term deleterious effects of anesthetic exposure early in life on cognitive development, with multiple exposures to general anesthetics being particularly damaging. We sought to determine whether repeated exposure of neonatal rats to anesthesia was associated with long-term cognitive impairments and whether the magnitude of impairments was greater than that resulting from a single exposure. Male or female Long-Evans rat pups were exposed to 1.8% isoflurane for 2 h on postnatal day (P) 7, or for 2 h each on P7, P10, and P13. Testing in a spatial working memory task began on P91. Rats that were repeatedly exposed to isoflurane were impaired relative to controls in the spatial working memory task. Male rats that received a single exposure to isoflurane showed an unexpected facilitation in spatial memory performance. These results support the hypothesis that multiple neonatal exposures to general anesthesia are associated with greater long-term cognitive impairment than a single exposure. The findings are congruent with human epidemiological studies reporting long-term cognitive impairments following multiple but not single general anesthetics early in life.

Keywords: Hippocampus; anesthetic neurotoxicity; cognitive impairment; neurodevelopment; pediatric anesthesia.

Figure 1

Radial arm maze performance parameters for male (A,C,E) and female (B,D,F) rats exposed to 2 h isoflurane at postnatal day (P) 7 (group 1A) or P7, P10, and P13 (group 3A), or 2 h control condition (group C). Time = time required to obtain all 12 food rewards up to a maximum of 900 s; Choices = the number of arm choices made during a trial before the first error occurred; Omissions = the number of unvisited arms at the end of a trial. *p ≤ 0.05.