Selective induction of astrocytic gliosis generates deficits in neuronal inhibition

Ortinski, Pavel I.; Dong, Jiajia; Mungenast, Alison E.; Yue, Cuiyong; Takano, Hajime; Watson, Deborah; Haydon, Philip G.; Coulter, Douglas A.

doi:10.1038/nn.2535

Cited by 416 publications

(386 citation statements)

References 37 publications

Supporting

Mentioning

359

Contrasting

Unclassified

Order By: Relevance

“…astrocytes were shown to promote either neuronal hyperexcitability 50 or inhibition, 51,52 thereby causing neural network dysfunction. Thus, the observation of increasing numbers of activated microglial cells and reactive astrocytes around plaques the longer the symptom duration supports a critical role of these nonneuronal cells in the progression of the disease.…”

Section: Discussionmentioning

confidence: 99%

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Serrano-Pozo

Betensky

Frosch

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312 þ dystrophic neurites, GFAP þ reactive astrocytes, and IBA1 þ and CD68 þ activated microglia in randomly selected dense-core (Thioflavin-S þ ) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall t Z 0.34, P Z 0.001), reactive astrocytes (Kendall t Z 0.30, P Z 0.003), and CD68 þ (Kendall t Z 0.48, P < 0.0001), but not IBA1 microglia (Kendall t Z 0.045, P Z 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68 þ microglia and symptom duration remained significant (Kendall t Z 0.39, P Z 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline. (Am J Pathol 2016, 186: 375e384; http://dx

show abstract

Section: Discussionmentioning

confidence: 99%

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Serrano-Pozo

Betensky

Frosch

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…The combination of GFAP GfaABC 1 D promoter with AAV of the serotype 5 is critical to achieve the specificity. One limitation of the technique described here is that virus infection and surgery procedure may cause astrocyte reactivity, especially with high-titer viruses 19 . Importantly, in the current study, AAV2/5 microinjections with a relative low titer did not cause decreases in GS that have been associated with astrocyte reactivity 19 .…”

Section: Discussionmentioning

confidence: 99%

“…One limitation of the technique described here is that virus infection and surgery procedure may cause astrocyte reactivity, especially with high-titer viruses 19 . Importantly, in the current study, AAV2/5 microinjections with a relative low titer did not cause decreases in GS that have been associated with astrocyte reactivity 19 . Similar controls have been reported for hippocampal astrocytes 8 .…”

Section: Discussionmentioning

confidence: 99%

Imaging Intracellular Ca<sup>2+</sup> Signals in Striatal Astrocytes from Adult Mice Using Genetically-encoded Calcium Indicators

Jiang¹,

Haustein²,

Sofroniew³

et al. 2014

JoVE

View full text Add to dashboard Cite

Astrocytes display spontaneous intracellular Ca 2+ concentration fluctuations ([Ca 2+ ] i ) and in several settings respond to neuronal excitation with enhanced [Ca 2+ ] i signals. It has been proposed that astrocytes in turn regulate neurons and blood vessels through calcium-dependent mechanisms, such as the release of signaling molecules. However, [Ca 2+ ] i imaging in entire astrocytes has only recently become feasible with genetically encoded calcium indicators (GECIs) such as the GCaMP series. The use of GECIs in astrocytes now provides opportunities to study astrocyte [Ca 2+ ] i signals in detail within model microcircuits such as the striatum, which is the largest nucleus of the basal ganglia. In the present report, detailed surgical methods to express GECIs in astrocytes in vivo, and confocal imaging approaches to record [Ca 2+ ] i signals in striatal astrocytes in situ, are described. We highlight precautions, necessary controls and tests to determine if GECI expression is selective for astrocytes and to evaluate signs of overt astrocyte reactivity. We also describe brain slice and imaging conditions in detail that permit reliable [Ca 2+ ] i imaging in striatal astrocytes in situ. The use of these approaches revealed the entire territories of single striatal astrocytes and spontaneous [Ca 2+ ] i signals within their somata, branches and branchlets. The further use and expansion of these approaches in the striatum will allow for the detailed study of astrocyte [Ca 2+ ] i signals in the striatal microcircuitry. Video LinkThe video component of this article can be found at

show abstract

“…The adenoassociated viral vectors used to deliver the GECIs have been shown previously to cause reactive gliosis of astrocytes 33 . Preparation of brain slices in general likely initiates early stages of pathology including release of inflammatory molecules 10 .…”

Section: Discussionmentioning

confidence: 99%

Inducing Plasticity of Astrocytic Receptors by Manipulation of Neuronal Firing Rates

Xie

Lauderdale

Murphy

et al. 2014

JoVE

View full text Add to dashboard Cite

Close to two decades of research has established that astrocytes in situ and in vivo express numerous G protein-coupled receptors (GPCRs) that can be stimulated by neuronally-released transmitter. However, the ability of astrocytic receptors to exhibit plasticity in response to changes in neuronal activity has received little attention. Here we describe a model system that can be used to globally scale up or down astrocytic group I metabotropic glutamate receptors (mGluRs) in acute brain slices. Included are methods on how to prepare parasagittal hippocampal slices, construct chambers suitable for long-term slice incubation, bidirectionally manipulate neuronal action potential frequency, load astrocytes and astrocyte processes with fluorescent Ca 2+ indicator, and measure changes in astrocytic Gq GPCR activity by recording spontaneous and evoked astrocyte Ca 2+ events using confocal microscopy. In essence, a "calcium roadmap" is provided for how to measure plasticity of astrocytic GqGPCRs. Applications of the technique for study of astrocytes are discussed. Having an understanding of how astrocytic receptor signaling is affected by changes in neuronal activity has important implications for both normal synaptic function as well as processes underlying neurological disorders and neurodegenerative disease. Video LinkThe video component of this article can be found at

show abstract

Selective induction of astrocytic gliosis generates deficits in neuronal inhibition

Cited by 416 publications

References 37 publications

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Imaging Intracellular Ca<sup>2+</sup> Signals in Striatal Astrocytes from Adult Mice Using Genetically-encoded Calcium Indicators

Inducing Plasticity of Astrocytic Receptors by Manipulation of Neuronal Firing Rates

Contact Info

Product

Resources

About