The general goal of this project is to understand the effects of brain injury due to hypoxia (HX) in the perinatal rodent;specifically this study will examine the astrocyte population of the subcortical white matter (WM) focusing on their development, their progeny and their ability to remove glutamate after HX. Altogether, my studies will define the specific effects of perinatal HX on astrocytes and the role of altered astrocyte development and function in WM injury. My results will not only shed light on crucial cellular and molecular mechanisms of WM injury and recovery, but may also assist in the development of new therapeutic approaches aimed at: i) enhancing WM recovery after early postnatal HX, and ii) reducing the long-term neurological sequelae associated with premature birth such as cerebral palsy, epilepsy, cognitive delay and learning disabilities. My overall hypothesis is that HX in the perinatal rodent induces changes in WM astrocyte function that directly affect oligodendrocyte integrity and development, and that this may be due to altered JAK/STAT signaling in astrocytes. I also hypothesize that HX promotes generation of oligodendrocytes from glial fibrillary acidic protein (GFAP)-expressing astrocytes. Therefore, I will determine the effect of HX on the expression of glial specific glutamate transporters GLAST and GLT-1 in the WM, and the ability of the WM to take up glutamate by two different approaches: electrophysiological characterization of WM astrocytes and uptake of radiolabled aspartate in WM crude membrane (synaptosome/gliosome) preparations. I will examine the effect of HX on JAK/STAT signaling in astrocytes and the effect of disrupting JAK/STAT signaling on the expression of GLAST and GLT-1. I will also perform lineage analysis studies, examining the progeny of GFAP- expressing astrocytes by utilizing an inducible Cre-recombinase system (hGFAP-Cre-ERT2 mouse) in which all progeny of GFAP-expressing cells are marked with a reporter to determine the contribution of these cells to WM recovery.
With improvements in neonatal care over the past two decades there has been an increase in the survival of preterm infants and this has been accompanied by a rise in the percentage of survivors of preterm birth who suffer some long-term neurological impairment. There is evidence that some of the brain injury in preterm infants may be due to a failure of oxygen delivery due to immature lungs and respiratory system (hypoxia). The proposed study focuses on analyzing the effect of hypoxia on subcortical white matter structures of the brain, in order to determine cellular and molecular mechanisms responsible for white matter injury and the results of the proposed study may assist in the development of new therapeutic approaches aimed at enhancing white matter recovery after hypoxia and at reducing long-term neurological morbidity.
|Raymond, Matthew; Li, Peijun; Mangin, Jean-Marie et al. (2011) Chronic perinatal hypoxia reduces glutamate-aspartate transporter function in astrocytes through the Janus kinase/signal transducer and activator of transcription pathway. J Neurosci 31:17864-71|