Synapses are specialized cell adhesions that are the fundamental functional units of the nervous system, but the extracellular signals that induce CNS synapse formation and function are poorly understood. We have been investigating the role of astrocytes in the formation and function of excitatory synapses in vitro and in vivo. Using retinal ganglion cells (RGCs) as a model CNS neuron, we recently found that astrocytes release several proteins that strongly enhance the formation and function of excitatory synapses onto RGCs. We identified thrombospondins as astrocyte-derived proteins that normally help to promote CNS synaptogenesis in vivo and are sufficient to induce ultrastructurally normal synapses in vitro. However we found that thrombospondin-induced synapses are postsynaptically silent, lacking AMPA glutamate receptors. The AMPA subtype of glutamate receptors mediates fast excitatory synaptic transmission, and regulated trafficking of AMPA receptors is an important mechanism for controlling synaptic strength. We have therefore used biochemistry to investigate the identity of the astrocyte-secreted signal that enhances the number of synaptic glutamate receptors, and in our preliminary results we have identified this signal. In this application, we will first test the hypothesis that the regulated release of this signal from astrocytes controls synaptic glutamate responsiveness by controlling AMPA receptor trafficking in vitro and in vivo. Second, we will test the hypothesis that the astrocyte-secreted factor acts through a candidate neuronal receptor. These studies are important for several reasons. First they have the potential to yield new insight into the mysterious roles of astrocytes in the development, function, and plasticity of the CNS. Second, these studies have the potential to yield new insight into the basic mechanisms that control synaptic plasticity and glutamate receptor responsiveness. Understanding the mechanisms that regulate synaptogenesis and synaptic plasticity are crucial to understanding the neural basis of learning and memory, Alzheimer?s disease, drug addiction, and epilepsy.

Public Health Relevance

Synapses are specialized cell adhesions that are the fundamental functional units of the nervous system, but the extracellular signals that induce CNS synapse formation and function are poorly understood. We have found that astrocytes profoundly enhance synapse formation and function and are identifying the molecular identity of these astrocyte-derived signals. Understanding the mechanisms that regulate synaptogenesis and synaptic plasticity are crucial to understanding the neural basis of learning and memory, Alzheimer's disease, drug addiction, and epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA015043-13
Application #
8416412
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Wu, Da-Yu
Project Start
2001-07-15
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
13
Fiscal Year
2013
Total Cost
$334,190
Indirect Cost
$126,765
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305