Hypoxic-ischemic brain injury exacerbates neuronal apoptosis and precipitates spontaneous seizures in glucose transporter isoform 3 heterozygous null mice

We examined the effects of 45‐min hypoxia (FiO2 0.08; Hx) vs. normoxia (FiO2 0.21; Nx) on the ipsilateral (Ipsi) and contralateral (Ctrl) sides of the brain in neuronal glucose transporter isoform 3 (Glut3) heterozygous null mice (glut3+/−) and their wild‐type littermates (WT), undergoing unilateral carotid artery ligation. Glut3+/− mice, under Nx, demonstrated a compensatory increase in blood–brain barrier/glial Glut1 protein concentration and a concomitant increase in neuronal nitric oxide synthase (nNOS) enzyme activity and Bax protein, with a decrease in procaspase 3 protein (P < 0.05 each). After Hx, reoxygenation in FiO2 of 0.21 led to no comparable adaptive up‐regulation of the ipsilateral brain Glut3 or Glut1 protein at 4 hr and Glut1 at 24 hr in glut3+/− vs. WT. These brain Glut changes in glut3+/− but not WT mice were associated with an increase in proapoptotic Bax protein and caspase‐3 enzyme activity (P < 0.01 each) and a decline in the antiapoptotic Bcl‐2 and procaspase‐3 proteins (P < 0.05 each). Glut3+/− mice after Hx demonstrated TUNEL‐positive neurons with nuclear pyknosis in most ipsilateral (hypoxic‐ischemia) brain regions. A subset (∼55%) of glut3+/− mice developed spontaneous seizures after hypoxic‐ischemia, confirmed by electroencephalography, but the WT mice remained seizure‐free. Pentylenetetrazole testing demonstrated an increased occurrence of longer lasting clinical seizures at a lower threshold in glut3+/− vs. WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic‐ischemic brain injury in glut3+/− mice exacerbates cellular apoptosis and necrosis and precipitates spontaneous seizures. © 2010 Wiley‐Liss, Inc.