Posts Tagged astrocyte

[Abstract + References] Neuron–glia interactions in the pathophysiology of epilepsy


Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.


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    Hochman, D. W. The extracellular space and epileptic activity in the adult brain: explaining the antiepileptic effects of furosemide and bumetanide. Epilepsia 53 (Suppl. 1), 18–25 (2012).

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    Giaume, C., Koulakoff, A., Roux, L., Holcman, D. & Rouach, N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat. Rev. Neurosci. 11, 87–99 (2010).

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    Deshpande, T. et al. Subcellular reorganization and altered phosphorylation of the astrocytic gap junction protein connexin43 in human and experimental temporal lobe epilepsy. Glia 65, 1809–1820 (2017).

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    Zeng, L. H., Bero, A. W., Zhang, B., Holtzman, D. M. & Wong, M. Modulation of astrocyte glutamate transporters decreases seizures in a mouse model of tuberous sclerosis complex. Neurobiol. Dis. 37, 764–771 (2010).

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    Campbell, S. L., Hablitz, J. J. & Olsen, M. L. Functional changes in glutamate transporters and astrocyte biophysical properties in a rodent model of focal cortical dysplasia. Front. Cell. Neurosci. 8, 425 (2014).

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    Eid, T. et al. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 28–37 (2004).This study establishes a key role of GS in astrocytes for maintaining an optimal level of extracellular glutamate through the glutamate–glutamine cycle.

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    van der Hel, W. S. et al. Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy. Neurology 64, 326–333 (2005).

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    Jiang, E., Yan, X. & Weng, H. R. Glial glutamate transporter and glutamine synthetase regulate GABAergic synaptic strength in the spinal dorsal horn. J. Neurochem. 121, 526–536 (2012).

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    Sada, N., Lee, S., Katsu, T., Otsuki, T. & Inoue, T. Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347, 1362–1367 (2015).

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    Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2017).

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    Tyzack, G. E. et al. Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression. Nat. Commun. 5, 4294 (2014).

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    Neniskyte, U. & Gross, C. T. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat. Rev. Neurosci.18, 658 (2017).

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    Chu, Y. et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc. Natl Acad. Sci. USA 107, 7975–7980 (2010).

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    Dityatev, A. Remodeling of extracellular matrix and epileptogenesis. Epilepsia 51, 61–65 (2010).

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    Dubey, D. et al. Increased metalloproteinase activity in the hippocampus following status epilepticus. Epilepsy Res. 132, 50–58 (2017).

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    Mizoguchi, H. & Yamada, K. Roles of matrix metalloproteinases and their targets in epileptogenesis and seizures. Clin. Psychopharmacol. Neurosci. 11, 45 (2013).

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    Arranz, A. M. et al. Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space. J. Neurosci. 34, 6164–6176 (2014).This study reports the first direct evidence for the development of seizures due to degradation of the ECM.

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    Rempe, R. G. et al. Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy. J. Neurosci. 38, 4301–4315 (2018).

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    Frischknecht, R. et al. Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat. Neurosci. 12, 897–904 (2009).This is one of the first studies to explain the molecular mechanism of ECM-regulated synaptic plasticity.

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    Balmer, T. S. Perineuronal nets enhance the excitability of fast-spiking neurons. eNeuro

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    Morawski, M. et al. Ion exchanger in the brain: quantitative analysis of perineuronally fixed anionic binding sites suggests diffusion barriers with ion sorting properties. Sci. Rep. 5, 16471 (2015).

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    Glykys, J. et al. Local impermeant anions establish the neuronal chloride concentration. Science 343, 670–675 (2014).This is one of the first studies to show the regulation of neuronal chloride homeostasis by the ECM.

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    Ye, Z.-C. & Sontheimer, H. Modulation of glial glutamate transport through cell interactions with the extracellular matrix. Int. J. Dev. Neurosci. 20, 209–217 (2002).

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    Guadagno, E. & Moukhles, H. Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4. 1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes. Glia 47, 138–149 (2004).

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    Seiffert, E. et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 7829–7836 (2004).This study provides the first direct evidence that BBB disruption contributes to epileptogenesis.

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    Ivens, S. et al. TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535–547 (2007).This study demonstrates the epileptogenic role of serum albumin and the TGFβ signalling in astrocytes following BBB disruption.

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    Kim, S. Y., Buckwalter, M., Soreq, H., Vezzani, A. & Kaufer, D. Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia 53 (Suppl. 6), 37–44 (2012).

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    Weissberg, I. et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol. Dis. 78, 115–125 (2015).

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    Salar, S. et al. Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures. Epilepsia 55, 1255–1263 (2014).

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    Kim, S. Y. et al. TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci. Rep. 7, 7711 (2017).

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    Bar-Klein, G. et al. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann. Neurol. 75, 864–875 (2014).

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via Neuron–glia interactions in the pathophysiology of epilepsy | Nature Reviews Neuroscience

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[NEWS] New study sheds light on why seizures happen after TBI


New study sheds light on why seizures happen after TBI

An astrocyte cell grown in tissue culture stained with antibodies 
Image Source: Gerry Shaw/Wikimedia Common

Researchers have known that severe or repeated brain injuries may trigger seizures in individuals for years, but why this is has remained a mystery. However, a new animal study published in the journal JNeurosci may provide some much-needed insight into the relationship between traumatic brain injury and epilepsy.

The study, conducted by Stefanie Robel, Oleksii Shandra, and colleagues, identified a unique cellular response to repeated brain injuries in mice that appears to contribute to the development of seizures similar to those experienced by humans after traumatic brain injury.

For the study, the team induced brain injuries in mice that are analogous to traumatic brain injury or concussions in humans. While observing the mice, the researchers also noticed that a unique group of astrocytes in the brain responded atypically to these injuries. The mice that showed this response also developed spontaneous recurrent seizures within one month.

In the case of severe traumatic brain injury, astrocytes may change to form a scar. This is important for allowing the brain, but these “scars” have also been linked to epilepsy. However, this scarification does not happen as a result of more mild traumatic brain injuries or concussions.

Instead, the researchers observed that the astrocytes responded in different ways almost immediately after the injury which were linked to later seizures.

At first, the team assumed the astrocytes were “dead” because they were no longer producing the proteins that characterize astrocytes. However, the team noticed they were in fact still working, but not responding to the injury in a unique way.

“Our experiments show a strong relationship between changes in astrocytes and the eventual occurrence of a seizure,” says Robel, an assistant professor with the Fralin Biomedical Research Institute and the School of Neuroscience in Virginia Tech’s College of Science.

“The findings point to a unique population of astrocytes that respond within 30 minutes of an injury being at the root of a problem where seizures may occur after a latency period of weeks or months, suggesting a therapeutic window to prevent seizure disorders after concussive injuries.”

via New study sheds light on why seizures happen after TBI – Neurologic Rehabilitation Institute

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[WEB SITE] Study uncovers genetic trigger that may help the brain to recover from stroke, other injuries

Scientists have found a genetic trigger that may improve the brain’s ability to heal from a range of debilitating conditions, from strokes to concussions and spinal cord injuries.

A new study in mice from UT Southwestern’s O’Donnell Brain Institute shows that turning on a gene inside cells called astrocytes results in a smaller scar and – potentially – a more effective recovery from injury.

The research examined spinal injuries but likely has implications for treating a number of brain conditions through gene therapy targeting astrocytes, said Dr. Mark Goldberg, Chairman of Neurology & Neurotherapeutics at UT Southwestern.

“We’ve known that astrocytes can help the brain and spinal cord recover from injury, but we didn’t fully understand the trigger that activates these cells,” Dr. Goldberg said. “Now we’ll be able to look at whether turning on the switch we identified can help in the healing process.”

The study published in Cell Reports found that the LZK gene of astrocytes can be turned on to prompt a recovery response called astrogliosis, in which these star-shaped cells proliferate around injured neurons and form a scar.

Scientists deleted the LZK gene in astrocytes of one group of injured mice, which decreased the cells’ injury response and resulted in a larger wound on the spinal cord. They overexpressed the gene in other injured mice, which stimulated the cells’ injury response and resulted in a smaller scar. Overexpressing the gene in uninjured mice also activated the astrocytes, confirming LZK as a trigger for astrogliosis.

Dr. Goldberg said a smaller scar likely aids the healing process by isolating the injured neurons, similar to how isolating a spreading infection can improve recovery. “But we don’t know under what circumstances this hypothesis is true because until now we didn’t have an easy way to turn the astrocyte reactivity on and off,” he said.

Further study is needed to analyze whether a compact scar tissue indeed improves recovery and how this process affects the neurons’ ability to reform connections with each other.

Dr. Goldberg’s lab will conduct more research to examine the effects of astrogliosis in stroke and spinal cord injuries. The researchers will determine whether turning up LZK in mice in advance of an injury affects its severity. They will then measure how the formation of the compact scar helps or hinders recovery.

“It has been a big mystery whether increasing astrocyte reactivity would be beneficial,” said Dr. Meifan Amy Chen, the study’s lead author and Instructor of Neurology at the Peter O’Donnell Jr. Brain Institute. “The discovery of LZK as an on switch now offers a molecular tool to answer this question.”


via Study uncovers genetic trigger that may help the brain to recover from stroke, other injuries

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[WEB SITE] How Brain Tissue Recovers Following an Injury – Neuroscience News

DECEMBER 16, 2016

Summary: Findings could lead to new treatments to help regeneration following trauma.

Source: Kobe University.

A research team led by Associate Professor Mitsuharu Endo and Professor Yasuhiro Minami has pinpointed the mechanism underlying astrocyte-mediated restoration of brain tissue after an injury. This could lead to new treatments that encourage regeneration by limiting damage to neurons incurred by reduced blood supply or trauma. The findings were published on October 11 in the online version of GLIA ahead of print release in January 2017.

When the brain is damaged by trauma or ischemia (restriction in blood supply), immune cells such as macrophages and lymphocytes dispose of the damaged neurons with an inflammatory response. However, an excessive inflammatory response can also harm healthy neurons.

Astrocytes are a type of glial cell, and the most numerous cell within the human cerebral cortex. In addition to their supportive role in providing nutrients to neurons, studies have shown that they have various other functions, including the direct or active regulation of neuronal activities.

It has recently become clear that astrocytes also have an important function in the restoration of injured brain tissue. While astrocytes do not normally proliferate in healthy brains, they start to proliferate and increase their numbers around injured areas and minimize inflammation by surrounding the damaged neurons, other astrocytes, and inflammatory cells that have entered the damaged zone. Until now the mechanism that prompts astrocytes to proliferate in response to injury was unclear.

The research team focused on the fact that the astrocytes which proliferate around injured areas acquire characteristics similar to neural stem cells. The receptor tyrosine kinase Ror2, a cell surface protein, is highly expressed in neural stem cells in the developing brain. Normally the Ror2 gene is “switched off” within adult brains, but these findings showed that when the brain was injured, Ror2 was expressed in a certain population of the astrocytes around the injured area.

Ror2 is an important cell-surface protein that regulates the proliferation of neural stem cells, so the researchers proposed that Ror2 was regulating the proliferation of astrocytes around the injured areas. They tested this using model mice for which the Ror2 gene did not express in astrocytes. In these mice, the number of proliferating astrocytes after injury showed a remarkable decrease, and the density of astrocytes around the injury site was reduced. Using cultured astrocytes, the team analyzed the mechanism for activating the Ror2 gene, and ascertained that basic fibroblast growth factor (bFGF) can “switch on” Ror2 in some astrocytes.

bFGF is produced in the injured zone of the cerebral cortex. Ror2 expression is induced in some population of the astrocytes that receive the bFGF signal, restarting their proliferation by accelerating the progression of their cell cycle. image is credited to Kobe University.

This research showed that in injured brains, the astrocytes that show (high) expression of Ror2 induced by bFGF signal are primarily responsible for starting proliferation. bFGF is produced by different cell types, including neurons and astrocytes in the injury zone that have escaped damage. Among the astrocytes that received these bFGF signals around the injury zone, some express Ror2 and some do not. The fact that proliferating astrocytes after brain injury are reduced during aging raises the possibility that the population of astrocytes that can express Ror2 might decrease during aging, which could cause an increase in senile dementia. Researchers are aiming to clarify the mechanism that creates these different cell populations of astrocytes.

By artificially controlling the proliferation of astrocytes, in the future we can potentially minimize damage caused to neurons by brain injuries and establish a new treatment that encourages regeneration of damaged brain areas.

Visit Site —> How Brain Tissue Recovers Following an Injury – Neuroscience News

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