Elsevier Editorial System(tm) for Current Opinion in Neurobiology
Title: Astrocytes partner with neurons during progression of neurological disease
Article Type: 22/5 Neurodevelopment and disease
Corresponding Author: Prof. Gail Mandel,
Corresponding Author's Institution:
First Author: James C McGann
Order of Authors: James C McGann; Daniel T Lioy; Gail Mandel
Astrocytes have fundamental roles in neurological disease progression.
In RTT and PD, astrocytes can independently cause disease phenotypes.
Much remains to be studied regarding the roles of astrocytes in other
More rigorous use of genetic tools should aid in these studies.
Astrocytes partner with neurons during progression of neurological disease
James C. McGanna, Daniel T. Lioya, and Gail Mandela,b
a Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239,
USA and Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
b Corresponding author: email@example.com
Click here to view linked References
As astrocytes are becoming recognized as important mediators of normal brain
function, studies into their roles in neurological disease have gained significance.
Across mouse models for neurodevelopmental and neurodegenerative diseases,
astrocytes are considered key regulators of disease progression. In Rett syndrome
and Parkinson’s disease, astrocytes can even initiate certain disease phenotypes.
Numerous potential mechanisms have been offered to explain these results, but
research into the functions of astrocytes in disease is just beginning. Crucially, in
vivo verification of in vitro data is still necessary, as well as a deeper understanding
of the complex and relatively unexplored interactions between astrocytes,
oligodendrocytes, microglia, and neurons.
Our understanding of the biological functions of glial cells (astrocytes, microglia, and
oligodendrocytes) in the nervous system is undergoing a transformation. Where
once they were considered accessories to the cognitively vital neurons, providing
only structural and trophic support, new research is describing a paradigm in which
glia are full partners with neurons in the operations of the brain. This includes roles
for astrocytes in regulating basal synaptic transmission [1,2] and synaptic efficacy
, eliciting slow inward currents [3,4], modulating cortical plasticity , and
numerous roles during development, including synaptogenesis . And as our
knowledge about astrocytic function in normal physiology has expanded,
exploration into their likely role in disease pathology has followed.
While microglia, oligodendrocytes, and astrocytes have been implicated in many
neurological disorders, here we focus on functional studies of astrocytes in mouse
models of genetic neurological diseases. Astrocytes are electrically inert cells that
are derived from the same progenitors as neurons. They come predominantly in two
forms, fibrous and protoplasmic, which denote their morphology and primary
location in the brain (white vs. grey matter, respectively). Glial Fibrillary Acidic
Protein (GFAP) is the most commonly used marker of mature astrocytes in the CNS
, though it is also expressed transiently by radial glia progenitors . Other
markers include Aldh1l1 , Glt-1, and GLAST . To date, no marker has been
identified that is expressed exclusively in mature astrocytes. Moreover, no pan-
astrocytic marker has been identified with which to determine the fraction of
astrocytes that are GFAP+, although recent studies on Aldh1L1 are promising .
Astrocytes undergo extreme morphological and molecular changes, including
upregulation of GFAP, after injury to the CNS by blunt trauma or neurodegeneration
. This process of astrogliosis is important to understand for clinical and
therapeutic reasons, and has a long a history of study that has been reviewed
extensively . In contrast, newly emerging roles for astrocytes in the early stages
of neurodevelopmental and neurodegenerative diseases have received less
attention. A broad study of the literature suggests that astrocytes are key regulators
of the progression of neuropathology after the first onset of disease. As described
below, astrocytes fundamentally affect the progression of disease in Rett syndrome,
Fragile X, amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s, and Parkinson’s.
In rare cases, astrocytes have been implicated in the initiation of some aspects of
disease, including in Rett syndrome and Parkinson’s disease, which suggests as-yet
unknown functions for astrocytes in normal brain function. From investigations into
the roles of glia during neurological disease, we are likely to achieve a broader
understanding of how the brain works, in addition to new insights into disease
diagnosis and treatment.
Astrocytes in neurodevelopmental disease
Astrocytes are born later in development than neurons, but are present when the
majority of synapses are formed. Recent evidence indicates that the close
association of neurons and astrocytes is necessary for normal synapse development,
including synaptic pruning [6,13]. This may have broad implications for
neurodevelopmental diseases, as problems may arise in synaptogenesis and
neuronal maturation due to astrocyte malfunction prior to the appearance of overt
Tuberous sclerosis complex (TSC)
One of the first neurodevelopmental disorders implicating astrocyte dysfunction
was tuberous sclerosis complex (TSC), which is caused by loss-of-function
mutations in the genes encoding HAMARTIN (TSC1) or TUBERIN (TSC2). TSC1 or 2
mutations lead to a hallmark increase in mTOR signaling  and brain dysplasia,
including the growth of non-malignant tumors called “tubers” (Reviewed by ).
Resected tubers from patients and mice harboring mutations in Tsc1 or 2 are
comprised mainly of enlarged, dysplastic astrocytes and neurons [16-19],
suggesting at least an indirect astrocytic component to the disease. To this point,
deletion of Tsc1 using a non-inducible hGFAP-cre transgene crossed to a
homozygous-floxed Tsc1 mouse resulted in some neurological features reminiscent
of the human disease . The authors concluded that this demonstrated an
astrocyte-specific growth advantage that resulted in the neuronal abnormalities.
However, this interpretation is likely confounded by hGFAP-cre activity in radial glia
A more tempered interpretation of the phenotype yielded by hGFAP-cre excision of
the Tsc genes was suggested when the transgene was used to knockout Tsc2 ,
which also yielded TSC-like neuropathology. In this case the authors interpreted the
results as demonstrating a role for Tsc2 in regulating the growth and differentiation
of GFAP+ radial glia cells. This interpretation seems more congruent with studies
showing that loss of Tsc2 selectively from neurons using a synapsin-I-cre transgene
 or a calcium-calmodulin kinase II-cre transgene  causes severe TSC-like
neuropathology. Further, removal of Tsc1 from forebrain progenitor cells using an
Emx1-cre  indicated that Tsc1 dysfunction does not lead to increased mTOR
signaling in astrocytes in vivo; however, non-canonical Tsc1/2-dependent signaling
pathways relevant to TSC neuropathology have been proposed [14,22]. It still
remains possible that astrocyte dysfunction contributes to TSC neuropathology,
especially given the presence of enlarged astrocytes in TSC patients and mouse
models, though a causal relationship between astrocyte dysfunction and TSC
symptoms will have to be reconciled with the robust phenotypes yielded by neuron-
specific deletion of Tsc2. One possibility is that Tsc1/2 mutation in neurons might
lead to secondary dysfunction in astrocytes necessary for disease progression. For
instance, loss of Tsc2 specifically from neurons causes astrogliosis , without
necessarily causing an increase in mTOR signaling in astrocytes . Further
experiments, especially with conditional knockouts, are necessary to determine
whether astrocyte dysfunction contributes to TSC neuropathology.
Rett Syndrome (RTT)
Rett syndrome is caused by sporadic loss-of-function mutations in the gene
encoding methyl-CpG-binding protein 2 (MECP2). MeCP2 is a transcription factor that
binds to methylated-CpGs throughout the genome , and was originally
suggested to act as a suppressor of proximal genes by recruiting histone
deacetylases and other co-repressors . Other functions for MeCP2 have now
been proposed including transcriptional activation , RNA processing , and
long-range gene repression . Genetic and behavioral studies initially suggested that
RTT neuropathology was due exclusively to MeCP2 dysfunction in neurons. Most
germane, loss of Mecp2 from subsets of neurons causes, to varying degrees of severity,
subsets of RTT-like phenotypes consistent with the known roles of the targeted neurons
[28-32]. Additionally, expression of Mecp2 in postmitotic neurons from the tau locus
prevents the appearance of some RTT-like phenotypes . Finally,
immunohistochemical analyses from laboratories studying RTT initially did not detect
MeCP2 in glia, including astrocytes [29,34,35]. However, western blot  and
chromatin immunoprecipitation  analyses indicated that astrocytes express MeCP2
protein in vitro. These results were advanced by more detailed analyses demonstrating
the presence of MeCP2 protein in astrocytes [38,39], as well as oligodendrocytes [38,40]
and microglia  in vitro and in vivo. Co-culture experiments showed that MeCP2 was
functional in astrocytes, because MeCP2-deficient astrocytes could not support normal
dendritic morphology in wild type neurons [38,39], while wild type astrocytes supported
normal dendritic architecture in MeCP2-deficient neurons . In addition, MeCP2
deficiency was reported to spread to wild-type astrocytes through gap junctions in culture
, potentially exacerbating the pathological effect of astrocytic MeCP2 loss in
heterozygous females. This very interesting finding has not yet been confirmed in vivo.
To investigate the potential role of astrocytes in RTT neuropathology in vivo, an
inducible form of the hGFAP-cre transgene  was utilized to restore astrocytic MeCP2
in a RTT mouse model as well as remove MeCP2 selectively from astrocytes in a wild-
type background  (Figure 1). The hGFAP-cre activity was induced in mice
postnatally between three and four weeks of age to avoid recombination in GFAP+
progenitor cells. These studies showed that restoring MeCP2 in astrocytes in an otherwise
null background had an unexpectedly profound influence on disease progression, because
astrocyte-rescued mice showed significant improvements in several phenotypes,
including increased longevity, improved locomotor abilities, and normalized respiratory
patterns. Further, neuronal dendritic morphology, VGLUT1 (a synaptic transporter
protein) levels, and soma sizes were restored to wild type levels in regions of efficient
astrocytic MeCP2 restoration. Interestingly, loss of MeCP2 from astrocytes in an
otherwise wild type mouse resulted in irregular breathing, though it did not result in
lethality, and caused relatively mild impairments in motor parameters with no effect on
neuronal dendritic morphology. These data were interpreted as showing that astrocytes
largely control the progression of RTT neuropathology, while neurons control the
initiation of most RTT-like phenotypes, excepting breathing regularity. This
interpretation is also consistent with the ability of MeCP2 expression in post-mitotic
neurons to prevent the appearance of several key RTT-like phenotypes , and is
similar to the proposed role of astrocytes in genetic forms of ALS (see below).
How astrocytes influence the progression of RTT neuropathology remains unknown. One
possible mechanism is through the secretion of trophic factors such as brain derived
neurotrophic factor (BDNF) and cytokines , the levels of which are decreased in the
absence of MeCP2 in vivo. It is also possible that improved energy metabolism
contributes to the astrocyte-rescue, because the levels of the astrocyte-specific metabolite
myo-inositol are decreased in RTT brains [43,44]. For respiration, multiple groups have
shown that astrocytes in brainstem respiratory centers are chemosensitive and profoundly
influence the firing patterns of respiratory neurons via the release of ATP in response to
changes in extracellular CO2 concentrations . Intriguingly, MeCP2-deficient mice
have decreased CO2-sensitivity  and ATP levels are decreased in the brains of
MeCP2-deficient mice . It is possible that restoration of MeCP2 in astrocytes restores
chemosensitivity of the astrocytes, therefore positively influencing respiratory patterns.
Whatever the mechanism of rescue, it seems that wild type neurons do not require the
same astrocytic support as MeCP2-deficient neurons, suggesting that further investigation
into neuronal-glial interactions is necessary to determine precisely how astrocytes support
improved neuronal function. It will also be important to investigate the involvement of
other glial cell types, such as microglia , in the progression of RTT in vivo because
microglia cause glutamate-induced neurotoxicity in vitro .
Fragile X Syndrome (FXS)
Fragile X syndrome is the leading cause of inherited intellectual disability in boys
and is caused by CGG expansion in the 5’ non-coding region of the X-linked gene
Fragile X Mental Retardation Protein 1 (FMRP1). FMRP1 is expressed primarily in
the brains and gonads , and functions as a translational regulator of mRNAs,
including transcripts important for dendritic growth and synapse formation [48-
52]; however, it is currently unclear how the dysregulation of mRNA translation
gives rise to FXS. Studies using FMRP1-deficient mice have clearly shown the
involvement of neurons in FXS neuropathology . Recent evidence suggests that
astrocytes might also contribute to the neuropathology of FXS. During normal
development in mice, while FMRP1 protein expression increases in neurons, it
decreases in cells of the glial lineage , including astrocytes, such that adult
GFAP+ astrocytes do not express detectable levels of the protein in vitro or in vivo
. This raises the possibility that a primary defect in astrocytes, due to the
absence of FMRP1 activity during astrocyte differentiation, contributes to latent
defects in neuronal function. In support of this idea, in co-culture FMRP1-deficient
astrocytes cause decreased neuronal survival, stunted dendritic arbors, and
decreased presynaptic and postsynaptic clustering of protein aggregates in wild
type neurons . Conversely, wild type astrocytes support normal dendritic and
synaptic morphology in FMRP1-deficient neurons . It remains unclear how
these results might impact the FXS phenotype because it was later shown that the
defects in morphology of wild type neurons caused by FMRP1-deficient astrocytes
are transient , and the influence of astrocytes on neuronal morphology in FXS
mice in vivo is not known.
A leading model for how loss of FMRP1 causes neuropathology involves the activity
of the metabotropic glutamate receptor 5-protein (mGluR5) . In FMRP1-
deficient mice, protein synthesis is increased downstream of mGluR5 signaling, and
mGluR5 antagonists can ameliorate deficits in learning and memory as well as
normalize the long-term depression deficits in CA1 neurons. Further, preliminary
results from clinical trials using mGluR5-signaling inhibitors suggest that mGluR5
signaling is relevant to the human disease . Therefore, synaptic signaling
between neurons via mGluR5 is likely a critical contributor to FXS neuropathology.
Interestingly, astrocytes also express functional mGluR5, and it was recently
demonstrated that astrocytes can detect single-synaptic stimulation at excitatory
synapses via mGluR5 localized to the astrocytic processes that envelop synapses .
Upon this detection of glutamatergic signaling by mGluR5, astrocytes increase the
efficiency of transmission in CA1 pyramidal cells by releasing ATP, which activates
presynaptic neuronal adenosine A2A receptors. Whether, and how, mGluR5 signaling
via astrocytes contributes to the excitatory synaptic defects evident in FXS mice
should be explored further.
Astrocytes in neurodegenerative disease
Because astrocytes are key regulators of brain homeostasis and neuronal
metabolism, degenerative diseases may be caused by lack of important astrocytic
functions, such as glutamate uptake , or by over-reactive astrocytes that result
in neuropathology .
Amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis is a fatal motor neuron disease for which several
mouse models have been developed based on inherited dominant mutations of the
gene superoxide dismutase (SOD1). In these models, mutant SOD1 expression is
necessary and sufficient in motor neurons to initiate the disease, but progression
depends almost entirely on its presence in both microglia and astrocytes .
Interestingly, recent in vitro experiments show that astrocytes expressing mutant
SOD1 are toxic to even wild-type neurons . These results were specific to motor
neurons only, accurately reflecting the in vivo phenotype. Astrocytes derived from
human patients with both familial and sporadic ALS show similar neurotoxic results
, arguing that astrocytes may be key activators of disease, not just of the
degenerative processes that follow initiation.
Several groups have sought to test this hypothesis in vivo. Overexpressing the G86R
mutant of SOD1 selectively in astrocytes under the control of the GFAP promoter
does not cause motor neuron degeneration. However, transplanting glial
precursor cells from G93A mutant SOD1-expressing mice into the spinal cord of wild
type rats resulted in motor neuron loss near the transplants and mild behavioral
and electrophysiological symptoms associated with ALS. Perhaps there is some
developmental compensation in the transgenic model that is not observed in vitro or
in transplantations. It is also possible that different SOD1 mutations can affect
astrocytes differently, though in vitro results would argue against this . In
agreement with the idea that astrocytes are specifically important for progression,
removing mutant SOD1 from astrocytes using the GFAP:Cre transgene has no effect
on the onset of disease, but slowed the rate of progression and increased
longevity[67,68], similar to the results seen in RTT. Furthermore, transplantation of
wild-type astrocytes into mutant SOD1-expressing mice also extended survival and
attenuated motor neuron loss .
While clearly important for disease progression, insights into the mechanisms by
which astrocytes affect motor neuron degeneration are lacking. Interactions
between astrocytes and microglia are clearly important, as microgliosis is increased
when astrocytes express mutant SOD1 [66,68], and reduced when astrocytes are
wild type [67,69]. This activation of microglia is downstream of astrocytic signals, as
minocycline, a microglial inhibitor, was able to rescue astrocyte-induced motor
neuron degeneration . However, NF-B signaling does not appear to mediate
this or any neurodegenerative effect of astrocytes in ALS . Future investigations
into the interaction between astrocytes and microglia in this and other disease
models will be important to develop useful therapeutics.
Huntington’s Disease (HD)
Huntington’s disease is caused by the expansion of CAG (glutamine-encoding)
repeats in the huntingtin protein that leads to selective neurodegeneration of
striatal neurons. Wild type neurons co-cultured with astrocytes that overexpress a
mutant form of the huntingtin protein undergo apoptosis, suggesting that this
protein impairs glial support of neuronal cells . This may be associated with
increased excitotoxicity, as mutant astrocytes were unable to protect neurons
against glutamate- or NMDA-induced toxicity in vitro.
In vivo, expression of mutant huntingtin (160Q) under the control of the GFAP
promoter leads to age-dependant neurological phenotypes including weight loss,
hindlimb clasping, and worsening rotarod performance . While the animals die
shortly after becoming symptomatic, no degeneration of neurons occurs, indicating
that neuronal function is perturbed by astrocytes prior to cell death. When these
mice were crossed with a line expressing mutant huntingtin primarily in neurons,
they displayed more severe neurological symptoms and earlier death ,
supporting a role for astrocytes in disease severity if not neurodegeneration. Future
experiments using the genetic strategies outlined in Figure 2 might be useful to
explore the role of astrocytes in Huntington’s disease. Meanwhile, lentiviral
overexpression of mutant huntingtin in astrocytes leads to morphological and
molecular changes that are also seen in the human disease, though no reports on the
effects of this perturbation on neurological function or degeneration were reported
Parkinson’s Disease (PD)
Parkinson’s disease is characterized by the presence of -synuclein protein
inclusions in neurons throughout the nervous system and progressive
neurodegeneration of dopaminergic neurons in the substantia nigra (SN), which
leads to severe motor dysfunction. Several mouse models for this disease exist that
phenocopy the disease to varying degrees, including MPTP- and rotenone-induced
neurodegeneration, overexpression of mutant forms of -synuclein, or knockouts of
Parkinson’s-linked genes Parkin, PINK1, or DJ-1, . Media conditioned from
Parkin-null astrocytes leads to increased apoptosis in neuronal cultures . In
addition, DJ-1 knockout astrocytes lack the ability to protect neurons from
rotenone-induced neurodegeneration , providing a non-neuronal link between
these models of PD.
Exciting new results have shown that selective expression of mutant -synuclein
protein in astrocytes in vivo results in SN neurodegeneration, behavioral
dysfunction and shortened lifespan . In fact, 100% of the animals died after
three months, a much faster rate than when mutant -synuclein protein is
expressed under control of the Hu or PrP promoters, which express in fewer
astrocytes but more neurons [78,79]. This suggests that astrocytic dysfunction
might be crucial for disease initiation, not just for downstream neurodegenerative
effects. This might also explain how grafted neurons end up showing -synuclein
pathology in long term transplants [80,81]. To further support this, no neuronal-
specific knockouts of Parkinson’s-related genes have led to neurodegeneration in
the SN . Conditional astrocyte-specific knockouts in these genes would help
answer whether astrocytes are the primary cell type for disease initiation (Figure
Alzheimer’s Disease (AD)
Several mouse models of Alzheimer’s disease are generated by overexpression of
various truncations of the amyloid- (A) protein, which form A plaques in the
brain that, along with cognitive deficits and tau neurofibrillary tangles, are
diagnostic for AD . A pre-treatment of astrocytes leads to decreased neuronal
viability in vitro, and co-culture of astrocytes accelerates and exacerbates neuronal
death caused by A treatment [83,84]. These effects and inflammatory signals are
reduced by treatment with minocycline, suggesting that microglia are upstream of
astrocyte-induced cell death observed in this paradigm . These results need to
be verified in vivo (Figure 2).
A possible mechanism is suggested by the finding that A-induced microglia signal
an increase in the levels of the hemichannel protein connexin43 (Cx43) in
astrocytes, which leads to increased toxic glutamate and ATP release [85,86].
Blocking hemichannel release in vivo leads to improved memory without affecting
A plaque deposition , arguing that these downstream glial events are
important for the cognitive decline observed in this disease. Genetically ablating
hemichannel function in microglia and astrocytes in AD models should further
demonstrate their importance to disease pathology. Other proposed mechanisms
for the A-induced neurotoxicity of astrocytes include the activation of neutral
sphingomyelinase , overexpression of S100B , calcium dysregulation ,
and metabolic dysfunction . Furthermore, transplantation of wild-type
astrocytes into the brains of A-expressing mice resulted in A clearance ,
supporting the notion that astrocytes should be targets of therapeutic investigations
in the future.
An increasing body of evidence is accumulating that astrocytes are key regulators of
neurological disease, in both developmental and degenerative contexts. Numerous
mechanisms have been proposed for these effects, including glutamate
dysregulation, ATP release, metabolic deficiency, phagocytosis, and inflammatory
signaling. This highlights just how many important functions astrocytes, in addition
to microglia and oligodendrocytes, have in normal CNS physiology, and indicates
that much more remains to be learned about their roles in normal and diseased
states. Only once the complicated network of actions and reactions between these
cell types is untangled can we begin to address the true underlying causes of
neurological disorders, and have more hope of developing effective treatments.
Figure 1. Genetic Strategies for Recessive Diseases
When trying to determine the role of astrocytes in Rett syndrome, our lab used the
genetic strategies outlined here. These strategies are designed to cause knockouts
after the shared neural progenitor stage (Nestin+, GFAP+) by inducing excision in
differentiated neurons (Synapsin::Cre is merely one example) or differentiated
astrocytes (hGFAP::CreERT2 + tamoxifen). In this figure, Your Favorite Gene (YFG)
takes the place of MeCP2 from Rett. Blue indicates normal expression levels and
black indicates low or no expression. While useful, no Cre line is expressed in 100%
of the cell type indicated, and the extent of mosaic expression will influence the
interpretation of results.
Figure 2. Genetic Strategies for Dominant Diseases
Similar to Figure 1, these genetic strategies are designed to express the dominant
gene of interest (Dom) only after the shared neural progenitor stage. Blue indicates
wild type gene expression and red indicates expression or overexpression of the
dominant gene. Again, mosaic expression of Cre recombinase will influence result
The authors would like to thank Dr. Nurit Ballas and Dr. Paul Barnes for comments
on the manuscript and grants from the NIH and Rett Syndrome Trust Foundation to
GM. GM is an Investigator of the Howard Hughes Medical Institute.
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Control for all other
Is the gene required in any
Is the gene required in adult
Is expression of the gene in
astrocytes sufficient to
ameliorate the phenotype?
Is the gene required in
Is expression of the gene in
neurons sufficient to
ameliorate the phenotype?
Figure 1. Genetic Strategies for Recessive Diseases
Wild type Download full-text
Control for all other
Is expression in all cell types
sufficient to cause disease?
Is expression in astrocytes
necessary to cause disease?
Is expression in astrocytes
sufficient to cause disease?
Is expression in neurons
necessary to cause disease?
Is expression in neurons
sufficient to cause disease?
Figure 2. Genetic Strategies for Dominant Diseases