How Might Brain “Astrocytes” Alter Nerve Cell Connections and Contribute to Autism Spectrum Disorder?

Lay Summary

How might brain “astrocytes” alter nerve cell connections and contribute to Autism Spectrum Disorder?

This cellular imaging study in animal models will explore whether two genetically determined forms of autism spectrum disorder (ASD) have similar deleterious alterations in star-shaped cells, called “astrocytes,” that adversely affect brain development.

Two genetic forms of ASD are Rett’s syndrome, which occurs almost exclusively in girls, and Fragile X syndrome, which occurs predominately in boys. Prior research showed that defects occur in neurons. More recent research indicates that defects occur as well in other types of cells in the brain, including astrocytes. While there are billions of nerve cells in the brain, there are even more astrocytes. Research suggests that astrocytes can produce both advantageous and deleterious effects. In the developing brain, astrocytes have a key role in regulating nerve cells’ functions. If astrocytes are altered, however, they may adversely affect brain development.

The investigators hypothesize that both in Rett’s syndrome and Fragile X syndrome, as well as in other forms of ASD, there are common alterations in the astrocytes’ functioning that adversely affect their regulatory interactions with nerve cells that are forming synapses (communication junctions) with one another in the developing brain.

During development, the billions of neurons in the brain make trillions of synaptic connections with each other to pass electrochemical messages via “neurotransmitters” from one to another. Astrocytes surround neurons, and their star-shaped “processes” closely associate with synapses enabling astrocytes to effectively regulate neuronal synaptic function.

For instance, astrocyte processes serve as a physical barrier to limit the amount of neurotransmission at the synapse. Additionally, astrocyte “transporters” prevent unintended activation of neighboring synapses by taking up excess neurotransmitter. Alterations in an astrocyte’s transporters or location of its processes, however, can affect synaptic transmission and neuronal function. Mouse models of ASD have revealed such alterations in transporter levels.

To identify the extent of astrocytes’ alterations and of their physical interactions with neurons in Rett’s syndrome and Fragile X syndrome, the investigators will use two types of cellular imaging in mouse models of these disorders and compare them to findings in healthy mice. First they will compare the astrocytes’ physical processes and interactions with neuronal synapses, using “3-D serial block face scanning electron microscopy.” Next, they will examine where astrocyte transporters are located in relation to neuronal synapses, using “high resolution array tomography immunostaining.”

They anticipate that alterations in the proximity of astrocyte processes to synapses, or the number of crucial proteins on astrocyte processes at synapses, will negatively impact neuronal communication and network function in the mouse models. After characterizing core alterations in the mouse models, the investigators plan to see whether these same differences are seen in autopsied brain tissue samples from patients who have died.

Significance : Identification of physical alterations in astrocytes in these two genetically determined forms of ASD may lead to new approaches to prevention or treatment.

Abstract

Investigating astrocyte-synapse interactions in autism spectrum disorders

Autism spectrum disorders (ASD) affect 1 in 100 children in the USA and many cases have no identified cause. Despite this lack of common cause, symptoms are shared across multiple forms of ASD, suggesting there are common pathways that can be targeted therapeutically. Key features of genetic forms of ASD including Rett’s syndrome and Fragile X syndrome are not only due to defects in neurons, but due to defects in a class of glial cell called astrocytes. Astrocytes are the most abundant cell type in the brain and have important roles in brain development by regulating neuronal synapse formation, function and plasticity. In the mature brain astrocyte processes are closely associated with synapses. This association is important for synaptic function, for example astrocytes take up excess neurotransmitter via uptake transporters, and provide a physical barrier to limit activation of neighboring synapses by neurotransmitter spillover. Key functions of astrocytes are altered in some cases of ASD, including Fragile X syndrome where astrocyte transporter function is altered. In this project we will investigate the extent of these alterations and if they are conserved across multiple ASD models, focusing on Rett’s and Fragile X syndrome. In Aim 1 we will use serial block face scanning electron microscopy to determine if the number of synapses that have an astrocyte process associated with them, or the proximity of the astrocyte process to the synapse, is altered in ASD models. In Aim 2 we will use array tomography high resolution immunostaining to determine if the synaptic localization of crucial astrocytic proteins, including glutamate transporters and potassium channels, is altered in ASD. We hypothesize that alterations in the proximity of astrocyte processes to synapses, or the number of crucial proteins on astrocyte processes at synapses, will negatively impact neuronal communication and network function in ASD. In future we will extend this work to additional mouse models of ASD to determine if differences we detect are characteristic features of ASD. Once we have established the core alterations in astrocyte-synapse interactions in mouse models of ASD, we will apply these findings to human tissue samples to determine if these differences are conserved. This study will give insight into novel therapeutic targets and treatment approaches for ASD.