The brain has billions
of cells of which only 30% are neurons. Astrocytes are the
predominant cell type of the remaining 70%. Surprisingly,
astrocytes have not been studied in as much detail as neurons have.
Astrocytes are associated with numerous neurological conditions,
including injury, multiple sclerosis, autism, schizophrenia,
Alzheimer's and Parkinson's disease and brain tumors.
‘The emergence of astrocytes during brain tumor progression in a mouse model marked the onset of seizures and brain tumor invasion. An improved understanding of how brain tumors cause seizures can potentially lead to strategies to prevent them or treat them.’
Astrocytes play diverse roles in the brain, from supporting the
functions of neurons, participating in synapse formation and function
and in the release of neurotransmitters, to making the blood-brain
barrier and other functions. What is not known is whether all these
functions are carried out by different subpopulations of astrocytes.
Scientists at Baylor College of Medicine and Texas
Children's Hospital explored the cellular and functional diversity of the most
enigmatic, yet most abundant cell type in the brain. The findings have suggested that detecting brain tumors at the earliest possible stage and eliminating
them before seizures begin might be possible one day.
In the study, which is published in the journal Nature Neuroscience
the scientists report that the emergence of specific brain cells during
brain tumor progression in a mouse model marked the onset of seizures
and brain tumor invasion. An improved understanding of how brain tumors
cause seizures can potentially lead to strategies to prevent them or
"We began this project by studying normal brain cells," said
co-senior author Dr. Benjamin Deneen, associate professor in the Center
for Stem Cell and Regenerative Medicine at Baylor and the Neurological
Research Institute at Texas Children's Hospital.
"Although astrocytes are often broadly categorized as one cell
type, a lot of diversity exists in the functions carried out by these
cells," said co-senior author Dr. Chad Creighton, associate professor of
medicine and member of the Dan L Duncan Comprehensive Cancer Center
Division of Biostatistics at Baylor.
Better understanding the underappreciated astrocyte
The researchers took populations of mouse astrocytes, which until
now have been considered to be a cell type with little diversity, and
used molecular markers expressed on the cells' surface to divide the
cells into subpopulations according to the cell surface markers
expressed. They identified five subpopulations - the scientists called
them subpopulations A, B, C, D and E - each containing a unique
combination of cell surface markers. These subpopulations were
consistently present across several different regions of the brain.
Further studies showed that each subpopulation of astrocytes
expressed distinct sets of genes. These molecular signatures suggested
that each subpopulation might play different roles in the brain. In
particular, the scientists were interested in subpopulation C, which
expressed a significant number of genes associated with synapses, the
junctions that transmit nerve impulses that connect networks of neurons
in the brain.
The researchers compared the ability of the different
subpopulations of astrocytes to support the formation and function of
synapses between neurons.
"In the laboratory, we combined individual subpopulation of
astrocytes with neurons and measured synapse formation and function,"
said Deneen. "We found that neurons incubated with subpopulation C made
more synapses than neurons incubated with the other subpopulations."
Taken together, these results revealed that astrocytes in the
normal mouse brain comprise at least five distinct subpopulations that
differentially support synapse formation and function.
Linking astrocytes to human glioma
"Astrocytes are associated with numerous neurological conditions,
including injury, multiple sclerosis, autism, schizophrenia,
Alzheimer's and Parkinson's disease and brain tumors. Given that we
found diverse astrocyte subpopulations, we wondered whether these
subpopulations could also explain astrocyte contributions to a host of
different neurological diseases," Deneen said.
One of the interests of the Deneen lab is identifying mechanisms
that regulate astrocyte development and how these cells contribute to
neurological diseases, in particular human glioblastoma multiforme, the
most aggressive and deadly type of brain tumor. In these type of cancer,
about 80 percent of the tumor comprises transformed astrocyte-like
cells, and, just as in the case of normal brain tissue, the diversity of
these tumor cell subpopulations and functions in brain tumors had not
been studied in detail.
In this case, the scientists used a different approach to
determine whether astrocyte-like cells in human glioblastoma include
different astrocyte subpopulations.
"We used publicly available genomic datasets to help us
understand what distinguishes the different types of astrocytes from
each other," Creighton said. "The genomic datasets compile entire
genomes - all the genes - of different types of cells. Using this
resource, we discovered that each type of human astrocyte showed very
distinctive patterns of gene activation. It was by comparing these
patterns with patterns associated with brain cancer or with epilepsy,
using public data, that we discovered how specific types of astrocytes
appear to have roles in these diseases."
To support that astrocytes seemed to play a role in human
glioblastoma, the researchers genetically engineered two mouse models of
the disease and observed that the astrocyte subpopulations are also
present in mouse tumors. The subpopulations are also present in primary
human specimens of human glioblastoma multiforme.
Astrocytes and seizures
One striking characteristic of glioblastoma, which usually leads to the discovery of the tumor, is epileptic seizures.
On one occasion Deneen was talking with Dr. Jeffrey L. Noebels,
about this research. Noebels, who is professor of neurology,
neuroscience, and molecular and human genetics, director of the Blue
Bird Circle Developmental Neurogenetics Laboratory at Baylor and is a
leader in the field of epilepsy, asked Deneen, "do your mice with brain
tumors have seizures?" "They do," Deneen said.
This conversation led to planning a series of experiments in the
mouse models of glioma to determine the time scale of the seizures and
whether different sub populations of astrocyte-like cells within the
tumor were associated with seizures.
The results of these experiments showed that as the tumor grows,
the excitability of the adjacent neurons progressively increases.
70 days after birth, the mice had visible seizures that correlated
with the emergence of astrocyte subpopulation C. Further linking these
astrocyte-like subpopulations to seizures, the scientists showed that
subpopulation C expresses a significant number of genes linked to
While subpopulation C seems to be involved with seizures in the
mouse model of glioblastoma, subpopulations B and D showed they were
able to migrate more in laboratory assays than population C.
"Taken all together, the evidence from the mouse model of
glioblastoma indicates that as the tumor evolves, different
subpopulations of astrocyte-like cells develop within the tumor and
execute distinct functions that are related to two important tumor
characteristics, synaptic imbalance that can lead to seizures, and tumor
migration that can lead to tumor invasion of other tissues," Deneen
"Less than half of the patients with epilepsy caused by a brain
tumor can be helped with existing antiepileptic drugs," said Noebels,
co-author of the work. "We do not understand exactly how malignant cells
cause seizures, or why seizures persist after tumor surgery. Until now,
we could only study this brain tissue at later misleading stages. I am
excited that this next-generation experimental model in mice will allows
us to study, for the first time, the earliest effects of human tumors
on brain circuits before seizures actually begin and understand the
mechanisms. These studies would be a major advance in patient care,
allowing clinicians to bypass precious months spent searching for
effective therapy to stop seizures. Because seizures themselves damage
brain tissue, timely effective therapy is of the essence."