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 (FiO(2) 0.08; Hx) vs. normoxia (FiO(2) 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 FiO(2) 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.
Fung
Camille
C
Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California, USA.
Evans
Edward
E
Shin
Don
D
Shin
Bo-Chul
BC
Zhao
Yuanzi
Y
Sankar
Raman
R
Chaudhuri
Gautam
G
Devaskar
Sherin U
SU
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005455:Fluorescent Antibody Technique; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D012640:Seizures / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*
D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3