Neuron–glia interactions in the pathophysiology of epilepsy

Patel, Dipan; Tewari, Bhanu P.; Chaunsali, Lata; Sontheimer, Harald

doi:10.1038/s41583-019-0126-4

Cited by 303 publications

(314 citation statements)

References 147 publications

Supporting

Mentioning

296

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, pathogenic mutations in RORB have been identified in genetic forms of epilepsy (Rudolf et al, 2016). Since astrocyte dysfunction is considered a key pathological mechanism in epilepsy (Patel et al, 2019), these RORB mutations may act by blocking the induction of mature astrocyte genes protecting from epileptogenesis (Patel et al, 2019), such as the Rorb target Glul, whose deletion in astrocytes in the mouse causes seizures and neurodegeneration (Zhou et al, 2019), or the glutamate transporter Slc1a2, which has been shown to be mutated in epileptic encephalopathies (Epi, 2016).…”

Section: Discussionmentioning

confidence: 99%

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Lattke

Goldstone

Guillemot

2020

Preprint

View full text Add to dashboard Cite

Astrocytes have diverse functions in brain homeostasis. Many of these functions are acquired during late stages of differentiation when astrocytes become fully mature. The mechanisms underlying astrocyte maturation are not well understood. Here we identified extensive transcriptional changes that occur during astrocyte maturation and are accompanied by chromatin remodelling at enhancer elements. Investigating astrocyte maturation in a cell culture model revealed that in vitro-differentiated astrocytes lacked expression of many mature astrocyte-specific genes, including genes for the transcription factors Rorb, Dbx2, Lhx2 and Fezf2. Forced expression of these factors in vitro induced distinct sets of mature astrocytesspecific transcripts. Culturing astrocytes with FGF2 in a three-dimensional gel induced expression of Rorb, Dbx2 and Lhx2 and improved their maturity based on transcriptional and chromatin profiles. Therefore extrinsic signals orchestrate the expression of multiple intrinsic regulators, which in turn induce in a modular manner the transcriptional and chromatin changes underlying astrocyte maturation.

show abstract

Section: Discussionmentioning

confidence: 99%

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Lattke

Goldstone

Guillemot

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Excess glutamate release and xCT expression. Elevated extracellular glutamate is a key contributor to cortical hyperexcitability, SD, epileptiform activity, and excitotoxicity (26,33). Although a principal role of glia in glutamate homeostasis involves extracellular glutamate uptake via Glut1-mediated transport, astrocytes also regulate extracellular glutamate release via the cysteine/glutamate antiporter system xc-.…”

Section: Pathogenesis Of Peritumoral Hyperexcitability In An Immunocomentioning

confidence: 99%

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model

Hatcher¹,

Yu²,

Meyer³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…Astrocytes, as the most numerous glial cells in the CNS, play many essential roles in tissue homeostasis, synaptic transmission, and neuroimmune responses (Farina et al, 2007;Clarke and Barres, 2013). Accumulating compelling evidence suggests that aberrant astrocyte activation contributes to the pathophysiology of epilepsy (De Lanerolle et al, 2010;Yin et al, 2015;Patel et al, 2019). Together with epidemiological evidence that systemic inflammation increases an individuals' susceptibility to seizures by lowering their seizure threshold (Yuen et al, 2018), these studies provide the foundation for the hypothesis that inflammation is a critical modulator of brain excitability.…”

Section: Prenatal Insultsmentioning

confidence: 99%

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

2020

View full text Add to dashboard Cite

The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic-ischemic injury, perinatal stroke), and insults sustained during early postnatal life-such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological antiepileptogenic therapeutic strategies.

show abstract

Neuron–glia interactions in the pathophysiology of epilepsy

Cited by 303 publications

References 147 publications

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

Contact Info

Product

Resources

About