Astrocytes throughout the CNS provide an array of services for their neighboring neurons including removing transmitters following release and providing metabolic sustenance. The realization that astrocytes are not merely caretakers but are also intimately involved in the main purpose of the CNS, processing information, is recent. Although the responses of astrocytes cannot match the speed of neurons, they can alter the interactions between neurons by isolating or opening pathways of communication between adjacent synapses. Additionally, astrocytes communicate between themselves and, bi-directionally, with neurons by responding to alterations in ionic gradients, released neurotransmitters, and by releasing neuroactive substances.
The aim of the present research is to determine the ability of, and mechanisms by which, astrocytes alter the isolation of synapses from neighboring synapses by the extension and retraction of astrocytic lamellipodial processes. These objectives will be addressed using a combination of 2 photon microscopy to directly observe process elaboration, electrophysiology to measure synaptic strength, pharmacological manipulation of receptor activity, 2 photon photolysis of caged glutamate to rapidly activate receptors in dendritic spine-sized volumes, flash photolysis of intracellular caged calcium, and expression of normally absence glutamate- gated ion channels to alter calcium influx. These studies will uncover strategies to control the necessary but potentially damaging effects of releasing glutamate into the extracellular space. Disruption of glutamate clearance followed by excitotoxic damage has been implicated in a variety of neurological pathologies. In addition, in schizophrenia and major depression, glial cell number is subnormal suggesting diminished trophic support of neurons that likely contributes to the reduced neuronal size, density of dendritic spines, and levels of synaptic proteins, as well as the abnormalities observed in fMRI in these conditions. Understanding astrocyte plasticity and its role in synaptic function promises unique approaches to managing the abnormalities in transmission in mental disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS059656-02
Application #
7420947
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Talley, Edmund M
Project Start
2007-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$168,438
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239