Purinergic signaling in epilepsy

Rassendren, François; Audinat, Etienne

doi:10.1002/jnr.23770

Cited by 46 publications

(43 citation statements)

References 133 publications

(185 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is in full agreement with the idea that reactive astrocytes in different pathological conditions are characterized by an increased P2Y1 receptor signaling (Delekate et al, ; Kuboyama et al, ). Functional interactions between cytokines and the gliotransmitters glutamate and ATP are thought to contribute in promoting epileptic seizures (Rassendren & Audinat, ; Vezzani, Balosso, & Ravizza, ; Vezzani, Ravizza, Balosso, & Aronica, ). This does not exclude, however, that other cell types and pathways are involved or regulate this canonical signaling.…”

Section: Discussionmentioning

confidence: 99%

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

Nikolić

Shen

Nobili

et al. 2018

Glia

Self Cite

View full text Add to dashboard Cite

Epilepsy is characterized by unpredictable recurrent seizures resulting from abnormal neuronal excitability. Increasing evidence indicates that aberrant astrocyte signaling to neurons plays an important role in driving the network hyperexcitability, but the underlying mechanism that alters glial signaling in epilepsy remains unknown. Increase in glutamate release by astrocytes participates in the onset and progression of seizures. Epileptic seizures are also accompanied by increase of tumor necrosis factor alpha (TNFα), a cytokine involved in the regulation of astrocyte glutamate release. Here we tested whether TNFα controls abnormal astrocyte glutamate signaling in epilepsy and through which mechanism. Combining Ca2+ imaging, optogenetics, and electrophysiology, we report that TNFα triggers a Ca2+‐dependent glutamate release from astrocytes that boosts excitatory synaptic activity in the hippocampus through a mechanism involving autocrine activation of P2Y1 receptors by astrocyte‐derived ATP/ADP. In a mouse model of temporal lobe epilepsy, such TNFα‐driven astrocytic purinergic signaling is permanently active, promotes glial glutamate release, and drives abnormal synaptic activity in the hippocampus. Blocking this pathway by inhibiting P2Y1 receptors restores normal excitatory synaptic activity in the inflamed hippocampus. Our findings indicate that targeting the coupling of TNFα with astrocyte purinergic signaling may be a therapeutic strategy for reducing glial glutamate release and normalizing synaptic activity in epilepsy.

show abstract

Section: Discussionmentioning

confidence: 99%

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

Nikolić

Shen

Nobili

et al. 2018

Glia

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, the hippocampal astrocytic A 2A receptor may be an attractive pharmacological target to increase seizure threshold and manage therapeutically drugrefractory MTLE in alternative to the pure neurocentric view that dominated antiepileptic drugs research for decades [67]. The exact mechanism by which the A 2A receptor promotes excitability in epileptic human patients remains unknown and difficult to investigate given the scarcity of human brain samples available for functional studies.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Purinergic Signalling

View full text Add to dashboard Cite

Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus. Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

show abstract

“…High expression of K Ca 3.1 and K ir combined with low K V 1.3 may, for example, be the result of a "stimulation milieu" dominated by an augmented purinergic drive, likely to be the case in epilepsy because of increased synaptic release of ATP/UTP, or secretion from astrocytes. 43 In contrast, we have no idea what may drive K Ca 1.1 expression and suspect it could relate to a species difference.…”

Section: Future Directions Toward An Integrated View Of Kmentioning

confidence: 96%

Potassium channel expression and function in microglia: Plasticity and possible species variations

et al. 2017

View full text Add to dashboard Cite

Potassium channels play important roles in microglia functions and thus constitute potential targets for the treatment of neurodegenerative diseases like Alzheimer, Parkinson and stroke. However, uncertainty still prevails as to which potassium channels are expressed and at what levels in different species, how the expression pattern changes upon activation with M1 or M2 polarizing stimuli compared with more complex exposure paradigms, and -most importantlyhow these findings relate to the in vivo situation. In this mini-review we discuss the functional potassium channel expression pattern in cultured neonatal mouse microglia in the light of data obtained previously from animal disease models and immunohistochemical studies and compare it with a recent study of adult human microglia isolated from epilepsy patients. Overall, microglial potassium channel expression is very plastic and possibly shows species differences and therefore should be studied carefully in each disease setting and respective animal models.

show abstract

Purinergic signaling in epilepsy

Cited by 46 publications

References 133 publications

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Potassium channel expression and function in microglia: Plasticity and possible species variations

Contact Info

Product

Resources

About