Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter (MCT) isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

Abstract. The Placenta plays a pivotal role in the maternofetal exchange of substances. In the chorioallantoic placentas of rodents, maternal and fetal bloods come close in the labyrinth. Hemotrichorial placenta is formed in most of rodents including rat, mouse, and hamster. Three trophoblast layers composed of a single cytotrophoblast layer and two syncytiotrophoblast layers and endothelium of fetal capillaries lie between maternal and fetal circulations in the labyrinthine wall. Many gap junctions are present between syncytiotrophoblast layers. The double-syncytiotrophoblast layers connected by gap junctions serve as a structural basis of the placental barrier as well as a site of specific transfer of various substances. In the guinea pig placenta, only a single syncytiotrophoblast layer is formed, thereby it is classified as a hemomonochorial placenta. Endotheliochorial placenta was reported in the kangaroo rat. The ultrastructural features of the labyrinthine wall are described and discussed in relation to specific transplacental transfer of substances, especially glucose.

We examined the effects of 45 min hypoxia (FiO2 0.08, Hx) versus 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, a concomitant increase in neuronal nitric oxide synthase (nNOS) enzyme activity and Bax protein, with a decrease in pro-caspase 3 protein (p<0.05 each). After Hx, re-oxygenation 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 24hrs in glut3+/− versus WT. These brain Glut changes in glut3+/− but not WT mice were associated with an increase in pro-apoptotic Bax protein and caspase-3 enzyme activity (p<0.01 each) and a decline in the anti-apoptotic 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 sub-set (~55%) of glut3+/− mice developed spontaneous seizures after hypoxic-ischemia confirmed by electroencephalography while the WT mice remained seizure-free. Pentylenetetrazole testing demonstrated an increased occurrence of longer lasting clinical seizures at a lower threshold in glut3+/− versus WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic-ischemic brain injury in glut3+/− mice exacerbates cellular apoptosis, necrosis and precipitates spontaneous seizures.

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