The polyamines (PA), spermine (SPM) and spermidine (SPD), are reported to be neuroprotective and increase longevity. They are released in whole brain from unknown sources during neuronal activity and trauma. Our preliminary data indicate that endogenous SPM and SPD are predominantly stored in glial cells in brain and retina, not in neurons, but the enzymes that synthesize SPM and SPD are lacking in glial cells. We also find many conditions under which glia release PA. These findings lead us to the working hypothesis that SPM/SPD are novel glio-modulators released from and buffered within the glial syncytium. Neuronal excitation results in a fall of [Na+]o, [Ca2+]o and [H+]o together with increased [K+]o, providing conditions that facilitate opening of hemichannels in glia and release of SPM from glia to the neuronal environment. Increased extracellular SPM can then modulate neuronal receptors and channels. In this proposal we specifically ask: (i) what is the mechanism of SPM permeation and accumulation in glia, (ii) how is release of SPM regulated and (iii) what are the functional consequences of SPM bidirectional flux through the glial membrane? These questions will be addressed by examining mechanisms of SPM transport and the effects of SPM in the glial-neuronal network. Using a novel SPM-biosensor we will monitor extracellular SPM concentration changes during trauma and normal conditions. These studies will elucidate the roles of SPM as an extracellular signaling molecule between glia and neurons in physiological and pathological situations. The results will provide important information for future efforts to understand and minimize neuronal damage during stroke and ischemia.

Public Health Relevance

Project Narrative In this project we will determine the mechanisms of the polyamines spermine (SPM) and spermidine (SPD) accumulation in and release from glia and their role in the neuronal network. These studies will elucidate the roles of SPM/SPD as extracellular signaling molecules between glia and neurons in physiological and pathological conditions. The results will provide important information for future efforts to understand and minimize neuronal damage during K+-spreading depression, stroke, ischemia and epilepsy in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065201-03
Application #
8259184
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Bosetti, Francesca
Project Start
2010-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$309,354
Indirect Cost
$72,684
Name
Universidad Central Del Caribe
Department
Biochemistry
Type
Schools of Medicine
DUNS #
090534694
City
Bayamon
State
PR
Country
United States
Zip Code
00960
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