Autism spectrum disorders (ASDs) are psychiatric disorders highlighted by social and communicative dysfunction. These complex behavioral changes are caused by altered synaptic functioning in select brain regions. Studies have previously focused on altered neuronal development and maturation. In addition to these neuronal changes, more recent studies have implicated astrocytes, the major glial cell in the brain, as major contributors to the pathogenesis of ASDs. Astrocytes are integral components of the tripartite synapse. In this model astrocyte processes surround and/or associate with pre- and post-synaptic components and regulate neurotransmitter homeostasis and recycling, provide basic substrates for neuronal metabolism, sequester Ca2+ ions and promote synaptogenesis and synaptic remodeling. Astrocytes have also been implicated in the pathogenesis of animal models of inherited human ASDs;these include mice lacking methyl-CpG-binding protein 2 (MeCP2) or the fragile X mental retardation 1 (FMR1) gene. While astrocyte diversity has been recognized for over a century, the molecular and cellular mechanisms underpinning this diversity in vivo and the consequences for psychiatric disorders remain poorly understood. The purpose of this proposal is to characterize astrocyte diversity in subpopulations of gray matter astrocytes in two mouse models of ASDs. Our experiments are facilitated by two technical advances that permit the identification and molecular characterization of astrocytes in animal models of ASDs. First, we have produced a novel transgenic mouse line (BT4-mEGFP) in which astrocyte surface membranes are fluorescently tagged from embryonic development onward. Breeding of these fluorescently tagged astrocytes into genetic models of ASDs will permit astrocyte isolation by fluorescent activated cell sorting and subsequent gene profiling. We will establish how these gene defects alter the development of astrocytes, the association of astrocytes with synapses and the expression of astrocyte proteins identified in the gene profiling studies. These data will be extended by determining the three dimensional associations between astrocytes and synapses using automated serial electron microscopy. Our studies are based upon the overall hypotheses that astrocytes play two key roles in ASDs. First, they have abnormal associations with synapses, which results in altered neurotransmitter homeostasis and abnormal neuronal electrical activity. Second they have altered mitochondrial functions, deficient ATP production and Ca2+ buffering, which reduces their ability to provide basic nutrition to neurons. These studies will elucidate previousl unidentified roles of astrocytes in ASDs and will provide a critical genetic and ultrastructural framework for the development of future therapeutic strategies that target astrocyte function in treating or preventing ASDs.

Public Health Relevance

Autism Spectrum Disorders (ASDs) are debilitating behavioral disorders that often occur with other heritable diseases, such as Retts and FragileX syndromes. Previously assumed to affect only neurons, new evidence implicates another CNS cell, the astrocyte, in the pathogenesis of the behavioral abnormalities. Based on mouse models of Retts and Fragile X syndromes, this project will generate several new mouse lines to facilitate genetic, proteomic, and morphological studies of astrocytes. We will also adapt emerging three dimensional electron microscopic technology to study synapses and astrocytes at nanometer resolution. We will use these approaches to dissect astrocyte changes that contribute to ASDs and evaluate their potential as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH099588-01
Application #
8442525
Study Section
Special Emphasis Panel (ZMH1-ERB-M (06))
Program Officer
Anderson, Kathleen C
Project Start
2013-01-15
Project End
2017-11-30
Budget Start
2013-01-15
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$394,063
Indirect Cost
$144,063
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195