Abstract P235: Reduced Uterine Perfusion Pressure Impairs Seizure-induced Downregulation Of Neurotransmitter Transporters In Mice

Abstract

Preeclampsia, a hypertensive disorder of pregnancy, can advance to eclampsia, if new onsetseizures occur. Previous work showed increased susceptibility to chemically-induced seizures inthe reduced uterine perfusion pressure (RUPP) rat model of preeclampsia; however, theunderlying mechanisms are unknown. Because seizures occur due to neurotransmitter activityimbalance, we hypothesized that RUPP mice have elevated excitatory and reduced inhibitoryactivity and that seizures exacerbate this imbalance.Timed-pregnant SMA-GFP mice (n=5-6 per group/treatment) were subjected to sham or RUPPsurgery on gestational day (GD) 13.5 and seizures were induced using 40mg/kg pentylenetetrazolon GD18.5. Tissues were harvested 30 minutes post-seizure induction. Maximum seizure scoreswere similar in sham (4.7±0.3) and RUPP (4.5±0.3) mice; p=0.37. Fluorometric assay showsseizures increased [F (1, 16) = 5.99, p=0.03], while RUPP had no effect [F (1, 16) = 1.15, p=0.3]on hippocampal glutamate concentration. No pairwise differences were observed within the shamand RUPP groups exposed to seizures (p>0.05). Seizures increased [F (1, 16) = 6.96, p=0.02],while RUPP had no effect [F (1, 16) = 0.61, p=0.45] on GABA concentration, with no significantpairwise difference in GABA concentration (p>0.05).Western blot analysis shows seizures significantly reduced hippocampal NMDAR1 (1.0±0.5 vs0.6±0.96, p=0.02; 1.0±0.1 vs 0.6±0.0, p=0.04) and GABAAR receptor expression (1.0±0.4 vs0.35±0.1, p<0.5; 1.05±0.3 vs 0.3±0.1, p<0.05) in sham and RUPP mice. Following seizureexposure, vesicular glutamate transporter (VGLUT1: sham: 1.0±0.3 vs 0.5±0.1; p<0.01, RUPP:0.8±0.2 vs 0.6±0.1; p=0.11), excitatory amino acid transporter 1 (EAAT1: sham: 1.0±0.4 vs0.6±0.2; p=0.02, RUPP: 0.9±0.1 vs 0.6±0.2; p=0.17) and GABA transporter (GAT1: sham: 1.0±0.5vs 0.4±0.1, p=0.01; RUPP: 0.8±0.2 vs 0.5±0.1, p=0.12) was reduced in sham mice, but not RUPPmice.Although RUPP does not change baseline GABA or glutamate related receptor or transporterexpression, our findings suggest seizure-induced reductions in vesicular and astrocyticneurotransmitter transporters is impaired by the RUPP procedure. Ongoing studies assesswhether other receptors and transporters are affected.