We tested the hypothesis that developmental effects of repeated neonatal exposure to sevoflurane in rats are exacerbated by stressful experiences received later in life. Sprague-Dawley male rats received sequential exposures to 3% sevoflurane for two h on postnatal days (P) six, seven, and eight. After weaning at P21, rats were housed either in pairs in an enriched environment (EE) or singly in an enrichment-deprived environment (an adverse environment, AE). The hippocampal concentrations of brain-derived neurotrophic factor (BDNF), and synaptic markers were assessed at P8 and P53. The dentate gyrus neural progenitor proliferation was evaluated at P11 and P53 after administration of bromodeoyuridine (BrdU) at P8 to P10 and at P22 to P27, respectively. Neurobehavioural evaluations were performed at P49 to P53. Repeated sevoflurane exposure acutely reduced concentrations of BDNF, synaptic markers and neural progenitor proliferation. The sevoflurane group housed in the AE conditions (sevoflurane+AE) had decreased concentrations of BDNF and synaptic markers, and survival of new granule cells and impaired cognitive function compared with the control+AE, control+EE, and sevoflurane+EE groups. The neurobehavioural parameters in the sevoflurane+EE and control+EE groups were similar. Neurocognitive abnormalities induced by repeated neonatal exposure to sevoflurane can be aggravated by stressful conditions such as social isolation and enrichment deprivation.

The cellular mechanisms that underlie impaired brain function during phenylketonuria (PKU), the most common biochemical cause of mental retardation in humans, remain unclear. Acute application of L-Phe at concentrations observed in the PKU brain depresses glutamatergic synaptic transmission but does not affect GABA receptor activity in cultured neurons. If these depressant effects of L-Phe take place in the PKU brain, then chronic impairment of the glutamate system, which may contribute to impaired brain function, could be detected as changes in postsynaptic glutamate receptors. This hypothesis was tested by using a combination of liquid chromatography–mass spectrometry, patch-clamp, radioligand binding and western blot approaches in forebrain tissue from heterozygous and homozygous (PKU) Pah^enu2 mice. Brain concentrations of L-Phe were nearly six-fold greater in PKU mice (863.12 ± 17.96 µmol/kg) than in their heterozygous counterparts (149.32 ± 10.23 µmol/kg). This concentration is significantly higher than the K_B of 573 µM for L-Phe to compete for N-methyl-d-aspartate (NMDA) receptors. Receptor binding experiments with [³H]MK-801 showed significant up-regulation of NMDA receptor density in PKU mice. Consistent with the depressant effects of L-Phe, expression of NMDA receptor NR2A and (RS)–amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor Glu1 and Glu2/3 subunits was significantly increased, whereas expression of the NR2B subunit was decreased. There was no change in GABA α1 subunit expression. Given the role of the glutamatergic system in brain development and function, these changes may, at least in part, explain the brain disorders associated with PKU.