Astrocytes are critical for the proper formation, growth and maintenance of neurons and synaptic connections in the nervous system. In virtually all disorders of the brain, astrocytes contribute to the altered function or pathology. To date, the role of astrocytes in the genesis of neurodevelopmental disorders associated with autistic features has not been studied in detail. Most recently, we have shown that astrocytes can prevent the abnormal dendrite morphology and the dysregulated synapses that characterize Fragile X syndrome (FXS). With astrocytes critical to normal synaptic function, this team project will identify new astrocyte-based factors for the treatment of neuronal dysfunction using molecular, cellular and behavioral approaches.
With a focus on the interactions between astrocytes and neurons and the secreted molecules produced by astrocytes, a variety of complimentary techniques will be used to study how astrocyte specific factors and signaling molecules can correct/modulate the structure and physiology of Fragile X neurons. To address essential questions about the dysfunctional patterns of neuronal physiology, the team will combine imaging with brain slice electrophysiology and whole-cell patch clamp recording techniques on single neurons. These functional assessments with astrocytes from Fragile X or wildtype genotypes will identify the role of astrocytes in aspects of synaptic function and plasticity (synaptic scaling, long term potentiation, long term depression) that are altered in Fragile X neurons (and hence contribute to the autistic phenotype).
In addition to the available mouse models of Fragile X, conditional knockout mice will permit the team to express desired gene products under the control of specific promoters. With the opportunity to express or repress molecules in astrocytes, we will reveal aspects of astrocyte-neuron interactions that are critical to normal function and the expression of the autistic phenotype from the molecular to the behavioral level. Drosophila models of FXS will also be used to study aspects of synaptic development and function that are influenced by glial factors. With team expertise in both FXS mouse and Drosophila transgenic models, rigorous experimental data on the efficacy of astrocytes and their secreted factors to correct synaptic structure/function within developmental windows will be essential to help understand the neurobiology responsible for the Fragile X phenotype.
The prevalence of autism spectrum disorders (ASDs) is rising dramatically on a yearly basis and new interventional strategies are required to treat ASDs and related disorders like Fragile X syndrome. Altered communication between brain cells may lead to the defects responsible for the features that characterize autism and other neurodevelopmental brain disorders.
In the developing brain, a type of cell called the astrocyte is important for the proper growth and function of the brain. Astrocytes act as gatekeepers of healthy brain function by producing substances to ensure that the communication signals in the brain are normal. Astrocytes and the substances they make are affected in neurodevelopmental disorders like autism and in turn alter the brain functions that control learning, memory and behavior.
Our research will use different biological and genetic techniques to correct the communication patterns in the brain. By altering the signaling or by applying substances from normal astrocytes to Fragile X brain cells, the interventions by the team will offset the development of abnormal communication in the brain. Most importantly, the results will help determine ways to counteract the consequences of intellectual and social disabilities associated with autism. This type of research will lead to new interventional treatment strategies for social disability disorders.