A growing body of evidence suggests that astrocytes are critical for the support of normal neuronal function, and astrocyte dysfunction may contribute to a number of neurodegenerative diseases. One important function of astrocytes is to transport nutrients from capillaries to neurons. Much of the nutritional support is in the form of glucose;however, it has been theorized that an alternate pathway, involving lactate, may also be an important source of energy for neurons. Astrocytes produce high amounts of lactate through glycolysis, and lactate can be transported from astrocytes to neurons via distinct molecular subspecies- MCT1, MCT4 in astroglia and MCT2 on neurons. Recent in vivo studies suggest that excitatory transmission may be regulated- in part - by networked astrocyte regulation of neuronal metabolism. In vitro, exogenous lactate or co-culturing with astrocytes is able to prevent the neuronal cell death induced by glucose deprivation. This protective function of astrocytes is lost by treatment with inhibitors to astroglial lactate transporters MCT1 and MCT4. In this Proposal we will first determine if astroglial lactate export by MCT1 or MCT4 is necessary for neuronal survival in vitro. These studies will test the hypothesis that astroglial lactate export is a fundamental astroglial support pathway for neurons. We will then determine if astroglial lactate transporters MCT1/MCT4 are A) Participants in normal neuronal function/activity in vivo and B) are necessary for neuronal survival in vivo. We hypothesize that Astroglial MCT transporters are likely to be necessary for normal neuronal function. Finally we will determine if dysregulation of MCT expression contributes to the neurodegeneration in ALS models if and repair of this pathway is neuroprotective. Overall, we hypothesize that astrocytes support neurons via essential lactate transport/export thru astrocyte specific transporters MCT1/MCT4 and that this pathway is a significant part of astroglial dysfunction in neurodegeneration and contributes to motor neuron death in diseases like ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033958-18
Application #
8424294
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Gubitz, Amelie
Project Start
1995-05-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
18
Fiscal Year
2013
Total Cost
$335,832
Indirect Cost
$109,234
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Porambo, Michael; Phillips, Andre W; Marx, Joel et al. (2015) Transplanted glial restricted precursor cells improve neurobehavioral and neuropathological outcomes in a mouse model of neonatal white matter injury despite limited cell survival. Glia 63:452-65
Philips, T; Rothstein, J D (2014) Glial cells in amyotrophic lateral sclerosis. Exp Neurol 262 Pt B:111-20
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Lee, Youngjin; Morrison, Brett M; Li, Yun et al. (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443-8
Gao, Yuanzheng; Perkins, Emma M; Clarkson, Yvonne L et al. (2011) β-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis. J Neurosci 31:16581-90
Li, Yun; Sattler, Rita; Yang, Eun Ju et al. (2011) Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression. Neuropharmacology 60:1168-75
Yang, Yongjie; Vidensky, Svetlana; Jin, Lin et al. (2011) Molecular comparison of GLT1+ and ALDH1L1+ astrocytes in vivo in astroglial reporter mice. Glia 59:200-7

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